KR20200031659A - Dosage regimen of anti-LAG-3 antibody and use thereof - Google Patents

Abstract

Dosage regimens for antibody molecules that specifically bind LAG-3 are disclosed. Antibody molecules can be used to treat or prevent cancerous or infectious conditions and disorders.

Description

Dosage regimen of anti-LAG-3 antibody and use thereof

Cross reference to related applications

This application claims the benefit of U.S. Provisional Application No. 62 / 534,798 filed on July 20, 2017 and U.S. Provisional Application No. 62 / 643,992 filed on March 16, 2018. The contents of the above application are incorporated herein by reference in their entirety.

Sequence Listing

This application contains a sequence listing which is submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy created on July 17, 2018 is named C2160-7019WO_SL.txt and is 233,727 bytes in size.

Lymphocyte activating gene-3, or LAG-3 (also known as CD223) is a member of the immunoglobulin supergene family, activated T cells (Huard et al. (1994) Immunogenetics 39: 213), NK cells ( Triebel et al. (1990) J. Exp. Med. 171: 1393-1405), regulatory T cells (Huang et al. (2004) Immunity 21: 503-513; Camisaschi et al. (2010) J Immunol. 184: 6545-6551; Gagliani et al. (2013) Nat Med 19: 739-746), and plasmacytoid dendritic cells (DC) (Workman et al. (2009) J Immunol 182: 1885-1891). LAG-3 is a membrane protein encoded by a gene located on chromosome 12 and is structurally and genetically related to CD4.

Similar to CD4, LAG-3 can interact with MHC class II molecules on the cell surface (Baixeras et al. (1992) J. Exp. Med. 176: 327-337; Huard et al. (1996) Eur. J. Immunol. 26: 1180-1186). Direct binding of LAG-3 to MHC class II has been suggested to serve to down-regulate antigen-dependent stimulation of CD4 ⁺ T lymphocytes (Huard et al. (1994) Eur. J. Immunol. 24: 3216- 3221), LAG-3 blockade is also a tumor or self-antigen (Gross et al. (2007) J Clin Invest. 117: 3383-3392) and virus model (Blackburn et al. (2009) Nat. Immunol. 10:29 -37) in both it was suggested to reactivate CD8 ⁺ lymphocytes. Additionally, the intracellular region of LAG-3 can interact with LAP (LAG-3-associated protein), a signaling molecule involved in downregulation of the CD3 / TCR activation pathway (Iouzalen et al. (2001) Eur J. Immunol. 31: 2885-2891). In addition, CD4 ⁺ CD25 ⁺ regulatory T cells (T _reg ) have been shown to express LAG-3 upon activation, which contributes to the inhibitory activity of T _reg cells (Huang, C. et al. (2004) Immunity 21: 503-513). LAG-3 can also negatively regulate T cell homeostasis by T _reg cells with both T cell-dependent and non-dependent mechanisms (Workman, CJ and Vignali, DA (2005) J. Immunol. 174: 688-695. ).

Thus, there is a need for novel therapeutic approaches to modulate LAG-3 function and function of LAG-3 expressing cells, including dosing regimens and agents for anti-LAG-3 antibody molecules, to treat diseases such as cancer. do.

Disclosed herein are antibody molecules (eg, humanized antibody molecules) that bind at least in part with high affinity and specificity to lymphocyte activating gene-3 (LAG-3). Pharmaceutical compositions and dosage formulations comprising anti-LAG-3 antibody molecules are also provided. Anti-LAG-3 antibody molecules disclosed herein are used to treat or prevent disorders, such as cancerous disorders (e.g., solid tumors and blood cancers), as well as infectious diseases (e.g., chronic infectious disorders or sepsis) ( Alone or in combination with other therapeutic agents, procedures or modalities). Accordingly, disclosed herein are methods, including dosing regimens, for treating various disorders using anti-LAG-3 antibody molecules. In certain embodiments, the anti-LAG-3 antibody molecule is administered or used in uniform or fixed doses.

Thus, in one aspect, the disclosure features a method of treating (eg, inhibiting, reducing, ameliorating or preventing) a disorder, such as a hyperproliferative condition or disorder (eg, cancer), in a subject.

In certain embodiments, the method provides the subject with an anti-LAG-3 antibody molecule, e.g., an anti-LAG-3 antibody molecule described herein, from about 300 mg to about 500 mg, from about 500 mg to about 700 mg, or about Dosage from 700 mg to about 900 mg, including once every 3 weeks or once every 4 weeks.

In certain embodiments, the anti-LAG-3 antibody molecule is administered once every 3 weeks or once every 4 weeks at a dose of about 300 mg to about 500 mg. In another embodiment, the anti-LAG-3 antibody molecule is administered once every 3 weeks or once every 4 weeks at a dose of about 500 mg to about 700 mg. In another embodiment, the anti-LAG-3 antibody molecule is administered once every 3 weeks or once every 4 weeks at a dose of about 700 mg to about 900 mg. In another embodiment, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to about 500 mg, about 500 mg to about 700 mg, or about 700 mg to about 900 mg. In another embodiment, the anti-LAG-3 antibody molecule is administered once every 4 weeks at a dose of about 300 mg to about 500 mg, about 500 mg to about 700 mg, or about 700 mg to about 900 mg.

In some embodiments, the anti-LAG-3 antibody molecule is about 300 mg to about 500 mg, for example about 350 mg to about 450 mg, about 300 mg to about 400 mg, or about 400 mg to about 500 mg, For example, it is administered once every three weeks at a dose of about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 350 mg to about 450 mg, such as about 400 mg.

In some embodiments, the anti-LAG-3 antibody molecule is about 500 mg to about 700 mg, for example about 550 mg to about 650 mg, about 500 mg to about 600 mg, or about 600 mg to about 700 mg, For example, it is administered once every four weeks at a dose of about 500 mg, about 533 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every 4 weeks at a dose of about 500 mg to about 650 mg, such as about 533 mg or about 600 mg.

In some embodiments, the anti-LAG-3 antibody molecule is about 700 mg to about 900 mg, for example about 750 mg to about 850 mg, about 700 mg to about 800 mg, or about 800 mg to about 900 mg, For example, it is administered once every four weeks at a dose of about 700 mg, about 750 mg, about 800 mg, about 850 mg, or about 900 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every four weeks at a dose of about 750 mg to about 850 mg, such as about 800 mg.

In some embodiments, the anti-LAG-3 antibody molecule is:

(a) 50% or more of soluble LAG-3 (e.g., 60% or more, 70% or more, 80% or more, 85% or more, 90% or more, 95% or more) in a subject (e.g., in the blood), 99% or more) are bound by anti-LAG-3 antibody molecules; or

(b) 50% or more (e.g., 60% or more, 70% or more, 80% or more, 85% or more, 90% or more, 95) of membrane-bound LAG-3 in a subject (e.g., in a cancer) % Or more, 99% or more) are bound by anti-LAG-3 antibody molecules

Doses or dose schedules that result in either or both.

In some embodiments, binding of the anti-LAG-3 antibody molecule to soluble LAG-3 is determined in a blood sample (eg, serum sample or plasma sample). In some embodiments, binding of the anti-LAG-3 antibody molecule to membrane-bound LAG-3 is determined in a cancer (eg, cancer sample).

In some embodiments, the subject has anti-LAG-3 binding of the anti-LAG-3 antibody molecule to soluble LAG-3, binding of the anti-LAG-3 antibody molecule to membrane-bound LAG-3, or both. It is determined when the antibody molecule has a steady state minimum level. In some embodiments, the lowest level is the concentration of the anti-LAG-3 antibody molecule about 24 weeks after administration, or the lowest concentration the anti-LAG-3 antibody molecule has reached before the next dose is administered. In some embodiments, binding of the anti-LAG-3 antibody molecule to soluble LAG-3, binding of the anti-LAG-3 antibody molecule to membrane-bound LAG-3, or both are in vitro (e.g., Determined by ELISA or cell-based assays or in vivo (eg, by imaging), measured for example, or predicted from a PK / PD model, eg, the PK / PD model described herein. .

In some embodiments, at least 60% of soluble LAG-3 in a serum sample from a subject is bound by an anti-LAG-3 antibody molecule. In some embodiments, at least 80% of soluble LAG-3 in a serum sample from a subject is bound by an anti-LAG-3 antibody molecule. In some embodiments, at least 90% of soluble LAG-3 in a serum sample from a subject is bound by an anti-LAG-3 antibody molecule.

In some embodiments, at least 85% of the membrane-bound LAG-3 in a cancer or cancer sample from a subject is bound by an anti-LAG-3 antibody molecule. In some embodiments, at least 90% of the membrane-bound LAG-3 in a cancer or cancer sample from a subject is bound by an anti-LAG-3 antibody molecule. In some embodiments, at least 95% of the membrane-bound LAG-3 in a cancer or cancer sample from a subject is bound by an anti-LAG-3 antibody molecule.

In some embodiments, 70% or more, 80% or more, or 90% or more of soluble LAG-3 in a serum sample from a subject is bound by an anti-LAG-3 antibody molecule and membrane in a cancer or cancer sample from the subject -85% or more, 90% or more, or 95% or more of the bound LAG-3 is bound by an anti-LAG-3 antibody molecule.

In some embodiments, at least 70% of soluble LAG-3 in serum samples from a subject is bound by an anti-LAG-3 antibody molecule, and 90% of membrane-bound LAG-3 in a cancer or cancer sample from a subject Abnormalities are bound by anti-LAG-3 antibody molecules. In some embodiments, at least 80% of soluble LAG-3 in a serum sample from a subject is bound by an anti-LAG-3 antibody molecule, and 90% of membrane-bound LAG-3 in a cancer or cancer sample from a subject Abnormalities are bound by anti-LAG-3 antibody molecules. In some embodiments, at least 90% of soluble LAG-3 in serum samples from a subject is bound by an anti-LAG-3 antibody molecule, and 90% of membrane-bound LAG-3 in a cancer or cancer sample from a subject Abnormalities are bound by anti-LAG-3 antibody molecules.

In certain embodiments, the anti-LAG-3 antibody molecule is from about 300 mg to about 800 mg, e.g., about 300 mg to about 500 mg (e.g., about 400 mg) or about 600 mg to about 800 mg ( For example, it is administered once every three weeks at a dose of about 700 mg). In some embodiments, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to about 500 mg (eg, about 400 mg).

In other embodiments, the anti-LAG-3 antibody molecule is from about 600 mg to about 1600 mg, for example from about 600 mg to about 1000 mg (e.g., about 800 mg) or from about 1200 mg to about 1600 mg ( For example, about 1400 mg) is administered once every 4 weeks. In some embodiments, the anti-LAG-3 antibody molecule is administered once every 4 weeks at a dose of about 600 mg to about 1000 mg (eg, about 800 mg).

In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose or dosage schedule that reduces one or both of the following:

(a) the level of free soluble LAG-3 in a subject (e.g., blood), e.g., 50% or less (e.g., 40% or less, 30% or less) of the reference level of free soluble LAG-3, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less); or

(b) the level of free membrane-bound LAG-3 in the subject (e.g., cancer), e.g., 50% or less (e.g., 40% or less) of the reference level of membrane-bound LAG-3 , 30% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less).

In some embodiments, the level of free soluble LAG-3 is determined in a blood sample (eg, serum sample or plasma sample). In some embodiments, the reference level of free soluble LAG-3 is the baseline level of free soluble LAG-3 in a subject, eg, according to a dosage schedule, e.g., prior to administration of an anti-LAG-3 antibody molecule.

In some embodiments, the level of free membrane-bound LAG-3 is determined in a cancer (eg, cancer sample). In some embodiments, the reference level of free membrane-bound LAG-3 is free membrane-bound LAG- in a subject, e.g., according to a dosage schedule, e.g., prior to administration of an anti-LAG-3 antibody molecule. This is the baseline level of 3.

In some embodiments, the level of free soluble LAG-3, the level of free membrane-bound LAG-3, or both, is determined when the subject has a steady state knockdown level of the anti-LAG-3 antibody molecule. In some embodiments, the lowest level is the concentration of the anti-LAG-3 antibody molecule about 24 weeks after administration, or the lowest concentration the anti-LAG-3 antibody molecule has reached before the next dose is administered. In some embodiments, the level of free soluble LAG-3, the level of free membrane-bound LAG-3, or both are in vitro (e.g., by ELISA or cell-based assays) or in vivo (e.g. , By imaging), or, for example, measured, or predicted from a PK / PD model, eg, the PK / PD model described herein.

In some embodiments, the level of free soluble LAG-3 is reduced to 30% or less of the reference level of free soluble LAG-3 in serum samples from subjects. In some embodiments, the level of free soluble LAG-3 is reduced to 20% or less of the reference level of free soluble LAG-3 in serum samples from subjects. In some embodiments, the level of free soluble LAG-3 is reduced to 10% or less of the reference level of free soluble LAG-3 in serum samples from subjects.

In some embodiments, the level of free membrane-bound LAG-3 is reduced to 15% or less of the reference level of free membrane-bound LAG-3 in a cancer or cancer sample from a subject. In some embodiments, the level of free membrane-bound LAG-3 is reduced to 10% or less of the reference level of free membrane-bound LAG-3 in a cancer or cancer sample from a subject. In some embodiments, the level of free membrane-bound LAG-3 is reduced to 5% or less of the reference level of free membrane-bound LAG-3 in a cancer or cancer sample from a subject.

In some embodiments, the level of free soluble LAG-3 is reduced to 30% or less, 20% or less, or 10% or less of the reference level of free soluble LAG-3 in a serum sample from a subject, and free membrane-bound LAG The level of -3 is reduced to 15% or less, 10% or less, or 5% or less of the reference level of free membrane-bound LAG-3 in a cancer or cancer sample from a subject.

In some embodiments, the level of free soluble LAG-3 is reduced to 30% or less of the reference level of free soluble LAG-3 in serum samples from the subject, and the level of free membrane-bound LAG-3 is cancer from the subject Or reduced to 10% or less of the reference level of free membrane-bound LAG-3 in cancer samples. In some embodiments, the level of free soluble LAG-3 is reduced to 20% or less of the reference level of free soluble LAG-3 in serum samples from the subject, and the level of free membrane-bound LAG-3 is cancer from the subject Or reduced to 10% or less of the reference level of free membrane-bound LAG-3 in cancer samples. In some embodiments, the level of free soluble LAG-3 is reduced to 10% or less of the reference level of free soluble LAG-3 in serum samples from the subject, and the level of free membrane-bound LAG-3 is cancer from the subject Or reduced to 10% or less of the reference level of free membrane-bound LAG-3 in cancer samples.

In certain embodiments, the anti-LAG-3 antibody molecule is from about 300 mg to about 800 mg, e.g., about 300 mg to about 500 mg (e.g., about 400 mg) or about 600 mg to about 800 mg ( For example, it is administered once every three weeks at a dose of about 700 mg). In some embodiments, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to about 500 mg (eg, about 400 mg).

In other embodiments, the anti-LAG-3 antibody molecule is from about 600 mg to about 1600 mg, for example from about 600 mg to about 1000 mg (e.g., about 800 mg) or from about 1200 mg to about 1600 mg ( For example, about 1400 mg) is administered once every 4 weeks. In some embodiments, the anti-LAG-3 antibody molecule is administered once every 4 weeks at a dose of about 600 mg to about 1000 mg (eg, about 800 mg).

In some embodiments, the disorder is cancer, eg, a cancer described herein. In certain embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a brain tumor, such as a glioblastoma, neuroeducational tumor, or recurrent brain tumor. In some embodiments, the cancer is pancreatic cancer, eg, advanced pancreatic cancer. In some embodiments, the cancer is skin cancer, such as melanoma (eg, stage II-IV melanoma, HLA-A2 positive melanoma, unresectable melanoma, or metastatic melanoma), or Merkel cell carcinoma. . In some embodiments, the cancer is renal cancer, eg, renal cell carcinoma (RCC) (eg, metastatic renal cell carcinoma). In some embodiments, the cancer is breast cancer, eg, metastatic breast carcinoma or stage IV breast carcinoma, such as triple negative breast cancer (TNBC). In some embodiments, the cancer is a virus-associated cancer. In some embodiments, the cancer is anal canal cancer (eg, squamous cell carcinoma of the anal canal). In some embodiments, the cancer is cervical cancer (eg, squamous cell carcinoma of the cervix). In some embodiments, the cancer is gastric cancer (eg, Epstein Barr virus (EBV) positive gastric cancer or gastric or gastro-esophageal junction carcinoma). In some embodiments, the cancer is head and neck cancer (eg, HPV positive and negative squamous cell head and neck cancer (SCCHN)). In some embodiments, the cancer is nasopharyngeal cancer (NPC). In some embodiments, the cancer is penile cancer (eg, squamous cell carcinoma of the penis). In some embodiments, the cancer is vaginal or vulvar cancer (eg, squamous cell carcinoma of the vagina or vulva). In some embodiments, the cancer is colorectal cancer, e.g., recurrent colorectal cancer or metastatic colorectal cancer, e.g., microsatellite unstable colorectal cancer, microsatellite stable colorectal cancer, mismatch recovery proficient colorectal cancer, or mismatch repair Deficient colorectal cancer. In some embodiments, the cancer is lung cancer, eg, non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is blood cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is a lymphoma, such as Hodgkin's lymphoma (HL) or diffuse versus B cell lymphoma (DLBCL) (eg, recurrent or refractory HL or DLBCL). In some embodiments, the cancer is myeloma.

In other embodiments, the cancer is a high-MSI cancer. In some embodiments, the cancer is metastatic cancer. In other embodiments, the cancer is advanced cancer. In other embodiments, the cancer is recurrent or refractory cancer. In other embodiments, the cancer is repetitive cancer.

In some embodiments, the anti-LAG-3 antibody molecule is about 300 mg to about 500 mg (e.g., about 400 mg), about 500 mg to about 700 by injection (e.g., intravenously or subcutaneously). mg (eg, about 533 mg or about 600 mg), or about 700 mg to about 900 mg (eg, about 800 mg) at a dose (eg, a uniform dose). The dosing schedule (eg, uniform dosing schedule) can vary, for example, once every 3 weeks to once every 4 weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered intravenously at a dose of about 300 mg to 500 mg (e.g., about 400 mg) once every three weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered intravenously once every 4 weeks at a dose of about 500 mg to 700 mg (e.g., about 533 mg or about 600 mg). In one embodiment, the anti-LAG-3 antibody molecule is administered intravenously at a dose of about 700 mg to 900 mg (e.g., about 800 mg) once every 4 weeks.

In one embodiment, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 400 mg intravenously to treat cancer disclosed herein. In one embodiment, the anti-LAG-3 antibody molecule is administered once every 4 weeks at a dose of about 533 mg or 600 mg intravenously to treat cancer disclosed herein. In one embodiment, the anti-LAG-3 antibody molecule is administered once every four weeks at a dose of about 800 mg intravenously to treat cancer disclosed herein.

In one embodiment, a method provides a subject with a PD-1 inhibitor (eg, an anti-PD-1 antibody molecule described herein) or a PD-L1 inhibitor (eg, an anti-PD-L1 antibody molecule described herein). It further comprises administering. In one embodiment, the PD-1 inhibitor (eg, the anti-PD-1 antibody molecule described herein) is administered intravenously at a dose of about 200 mg to about 400 mg (e.g., about 300 mg) every 3 weeks. It is administered once. In certain embodiments, a subject has an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) of about 200 mg to about 400 mg (e.g., about 300 mg) in combination with an anti-PD-1 antibody molecule. In certain embodiments, the anti-LAG-3 antibody molecule (e.g., anti-LAG-3 antibody molecule described herein) is 3 weeks in a dose of about 300 mg to about 500 mg (e.g., about 400 mg). Administered once per dose, and the PD-1 inhibitor (e.g., anti-PD-1 antibody molecule described herein) is 1 every 3 weeks at a dose of about 200 mg to about 400 mg (e.g., about 300 mg). Is administered once. In another embodiment, the subject has an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) of about 300 mg to about 500 mg (e.g., about 400 mg) in combination with an anti-PD-1 antibody molecule. In certain embodiments, the anti-LAG-3 antibody molecule (eg, the anti-LAG-3 antibody molecule described herein) is 4 weeks in a dose of about 600 mg to about 1000 mg (eg, about 800 mg) Administered once per dose, the PD-1 inhibitor (e.g., the anti-PD-1 antibody molecule described herein) is 1 every 4 weeks at a dose of about 300 mg to about 500 mg (e.g., about 400 mg). Is administered once. In one embodiment, the method provides the subject with an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) and a chemotherapeutic agent (e.g., a platinum agent (e.g. carbople) Latin, cisplatin, oxaliplatin, or tetraplatin) or nucleotide analogs or precursor analogs (eg, capecitabine)). In one embodiment, the chemotherapeutic agent (e.g., platinum agent, e.g. carboplatin) is intravenously administered with an area under the curve (AUC) of about 4 to about 8 or about 5 to about 7 (e.g., It is administered once every 3 weeks at a dose to achieve an AUC of about 6). In certain embodiments, the anti-LAG-3 antibody molecule (e.g., anti-LAG-3 antibody molecule described herein) is 3 weeks in a dose of about 300 mg to about 500 mg (e.g., about 400 mg). Administered once per chemotherapy agent (e.g., a platinum agent, e.g. carboplatin), has an area under the curve (AUC) of about 4 to about 8 or about 5 to about 7 (e.g., about AUC) of 6 is administered once every 3 weeks in a dose.

In one embodiment, a method provides an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein), a PD-1 inhibitor (e.g., an anti-PD-1 described herein) to a subject. Antibody molecules), and chemotherapeutic agents (e.g., platinum agents (e.g. carboplatin, cisplatin, oxaliplatin, or tetraplatin) or nucleotide analogs or precursor analogs (e.g. capecitabine)) Administration. In certain embodiments, the anti-LAG-3 antibody molecule (e.g., anti-LAG-3 antibody molecule described herein) is 3 weeks in a dose of about 300 mg to about 500 mg (e.g., about 400 mg). Administered once per dose, and the PD-1 inhibitor (e.g., anti-PD-1 antibody molecule described herein) is 1 every 3 weeks at a dose of about 200 mg to about 400 mg (e.g., about 300 mg). Administered once, the chemotherapeutic agent (e.g., a platinum agent, e.g., carboplatin) has an area under the curve (AUC) of about 4 to about 8 or about 5 to about 7 (e.g., about 6 AUC) is administered once every three weeks at a dose to achieve.

In certain embodiments, an anti-LAG-3 antibody molecule (eg, an anti-LAG-3 antibody molecule described herein), or a combination comprising an anti-LAG-3 antibody molecule (eg, PD-1 An anti-LAG-3 antibody molecule) in combination with one or both inhibitors or chemotherapeutic agents), for example, to treat breast cancer, e.g., triple negative breast cancer (TNBC), according to the dosing schedule described herein. Is used.

In certain embodiments, the subject has not been treated with PD-1 or PD-L1 therapy prior to receiving an anti-LAG-3 antibody molecule. In other embodiments, the subject has been treated with PD-1 or PD-L1 therapy prior to receiving anti-LAG-3 antibody molecules.

In certain embodiments, the subject is given a chemotherapeutic agent (e.g., a platinum agent (e.g. carboplatin, cisplatin, oxaliplatin, or tetraplatin)) or a nucleotide analog prior to receiving an anti-LAG-3 antibody molecule or Not treated with precursor analogs (eg, capecitabine). In another embodiment, the subject is given a chemotherapeutic agent (e.g., a platinum agent (e.g. carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide analog) prior to receiving an anti-LAG-3 antibody molecule or Treated with precursor analogs (eg, capecitabine).

In other embodiments, the subject has or is found to have LAG-3 expression in tumor-infiltrating lymphocytes (TILs).

In another aspect, the disclosure features a method of reducing the activity (eg, growth, survival or survival rate, or both) of hyperproliferative (eg, cancer) cells. The method comprises contacting the cell with an anti-LAG-3 antibody molecule, eg, the anti-LAG-3 antibody molecule described herein. The method can be used in a subject, e.g., as part of a treatment protocol, e.g., from about 300 mg to about 500 mg (e.g., about 400 mg), about 500 mg to about 700 mg of an anti-LAG-3 antibody molecule ( For example, it may be performed once every 3 weeks or once every 4 weeks at a dose of about 533 mg or about 600 mg), or about 700 mg to about 900 mg (eg, about 800 mg). In certain embodiments, the dose is about 300 mg to about 500 mg (eg, about 400 mg) of anti-LAG-3 antibody molecule once every three weeks. In another embodiment, the dose is about 500 mg to about 700 mg (e.g., about 533 mg or about 600 mg) of anti-LAG-3 antibody molecule once every 4 weeks. In other embodiments, the dose is about 700 mg to about 900 mg (eg, about 800 mg) of anti-LAG-3 antibody molecule once every 4 weeks.

Cancer cells include, for example, cancers described herein, such as solid tumors or blood cancers, such as brain tumors (eg, glioblastoma, neuroedema, or recurrent brain tumors), pancreatic cancer (eg, Advanced pancreatic cancer), skin cancer (e.g. melanoma (e.g. stage II-IV melanoma, HLA-A2 positive melanoma, unresectable melanoma or metastatic melanoma), or Merkel cell carcinoma), renal cancer (e.g. For example, renal cell carcinoma (RCC) (e.g., metastatic renal cell carcinoma)), breast cancer (e.g., metastatic breast carcinoma or stage IV breast carcinoma, e.g., triple negative breast cancer (TNBC)), virus- Associated cancer, anal duct cancer (e.g. squamous cell carcinoma of the anal duct), cervical cancer (e.g. squamous cell carcinoma of the cervix), gastric cancer (e.g. Epstein Barr virus (EBV) positive gastric cancer or stomach or stomach -Esophageal junction carcinoma), head and neck cancer (eg, HPV positive and negative squamous) Cell head and neck cancer (SCCHN), nasopharyngeal cancer (NPC), penile cancer (e.g. squamous cell carcinoma of the penis), vaginal or vulvar cancer (e.g. squamous cell carcinoma of the vagina or vulva), colorectal cancer (e.g. For example, recurrent colorectal cancer or metastatic colorectal cancer, e.g. microsatellite unstable colorectal cancer, microsatellite stable colorectal cancer, mismatch recovery proficient colorectal cancer, or mismatch recovery deficit colorectal cancer), lung cancer (e.g. Non-small cell lung cancer (NSCLC)), leukemia, lymphoma (e.g., Hodgkin's lymphoma (HL) or diffuse versus B cell lymphoma (DLBCL), e.g. recurrent or refractory HL or DLBCL), or from myeloma Cells.

In certain embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a brain tumor, such as a glioblastoma, neuroeducational tumor, or recurrent brain tumor. In some embodiments, the cancer is pancreatic cancer, eg, advanced pancreatic cancer. In some embodiments, the cancer is skin cancer, such as melanoma (eg, stage II-IV melanoma, HLA-A2 positive melanoma, unresectable melanoma, or metastatic melanoma), or Merkel cell carcinoma. . In some embodiments, the cancer is renal cancer, eg, renal cell carcinoma (RCC) (eg, metastatic renal cell carcinoma). In some embodiments, the cancer is breast cancer, eg, metastatic breast carcinoma or stage IV breast carcinoma, such as triple negative breast cancer (TNBC). In some embodiments, the cancer is a virus-associated cancer. In some embodiments, the cancer is anal canal cancer (eg, squamous cell carcinoma of the anal canal). In some embodiments, the cancer is cervical cancer (eg, squamous cell carcinoma of the cervix). In some embodiments, the cancer is gastric cancer (eg, Epstein Barr virus (EBV) positive gastric cancer or gastric or gastro-esophageal junction carcinoma). In some embodiments, the cancer is head and neck cancer (eg, HPV positive and negative squamous cell head and neck cancer (SCCHN)). In some embodiments, the cancer is nasopharyngeal cancer (NPC). In some embodiments, the cancer is penile cancer (eg, squamous cell carcinoma of the penis). In some embodiments, the cancer is vaginal or vulvar cancer (eg, squamous cell carcinoma of the vagina or vulva). In some embodiments, the cancer is colorectal cancer, e.g., recurrent colorectal cancer or metastatic colorectal cancer, e.g., microsatellite unstable colorectal cancer, microsatellite stable colorectal cancer, mismatch recovery proficient colorectal cancer, or mismatch repair Deficient colorectal cancer. In some embodiments, the cancer is lung cancer, eg, non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is blood cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is a lymphoma, such as Hodgkin's lymphoma (HL) or diffuse versus B cell lymphoma (DLBCL) (eg, recurrent or refractory HL or DLBCL). In some embodiments, the cancer is myeloma.

In certain embodiments, the method provides the cells with a PD-1 inhibitor (eg, an anti-PD-1 antibody molecule described herein) or a chemotherapeutic agent (eg, a platinum agent (eg, carboplatin, cisplatin). , Oxaliplatin, or tetraplatin) or nucleotide analogs or precursor analogs (eg, capecitabine)). The method is administered once every three weeks in a subject, e.g., as a part of a treatment protocol, e.g., at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) of an anti-LAG-3 antibody molecule, and It can be performed once every three weeks at a dose of about 200 mg to about 400 mg (eg, about 300 mg) of the PD-1 inhibitor. The method is administered to a subject once every 4 weeks, e.g., at a dose of about 600 mg to about 1000 mg (e.g., about 800 mg) of an anti-LAG-3 antibody molecule, e.g. as part of a treatment protocol, and It can be performed once every 4 weeks at a dose of about 300 mg to about 500 mg (eg, about 400 mg) of the PD-1 inhibitor. The method is administered once every three weeks in a subject, e.g., as a part of a treatment protocol, e.g., at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) of an anti-LAG-3 antibody molecule, and The chemotherapy agent may be performed once every three weeks at a dose to achieve an area under the curve (AUC) of about 4 to about 8 or about 5 to about 7 (eg, AUC of about 6). The method is administered to a subject once every three weeks, eg, as part of a treatment protocol, e.g., at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) of an anti-LAG-3 antibody molecule, Area under the curve of about 200 mg to about 400 mg (e.g., about 300 mg) of the PD-1 inhibitor once every 3 weeks, and about 4 to about 8 or about 5 to about 7 of the chemotherapeutic agent (AUC) can be performed once every three weeks at a dose to achieve (e.g., AUC of about 6). In some embodiments, the cancer cells can be, for example, breast cancer cells, such as TNBC cells. In certain embodiments of the methods disclosed herein, the method further comprises determining the level of LAG-3 expression in the subject's tumor infiltrating lymphocytes (TIL). In other embodiments, the level of LAG-3 expression is determined (eg, using immunohistochemistry) in a sample (eg, tumor biopsy) obtained from the subject. In certain embodiments, where there is a detectable or elevated level of LAG-3 in a subject, an anti-LAG-3 antibody molecule is administered (e.g., an anti-LAG-3 antibody molecule is LAG in a subject) -3 is administered in response to a detectable level or an elevated level). For example, to monitor the effectiveness of the therapeutic agents described herein, a detection step can also be used. For example, the detection step can be used to monitor the effectiveness of the anti-LAG-3 antibody molecule.

In another aspect, the disclosure provides a composition (eg, one or more compositions or dosage forms) comprising an anti-LAG-3 antibody molecule (eg, an anti-LAG-3 antibody molecule as described herein). It is characterized by. Formulations comprising anti-LAG-3 antibody molecules (e.g., anti-LAG-3 antibody molecules as described herein), e.g., administration formulations, and kits, e.g., treatment kits, are also described herein. . In certain embodiments, the composition or formulation is about 300 mg to about 500 mg (e.g., about 400 mg), about 500 mg to about 700 mg (e.g., about 533 mg or about 600 mg), or about 700 mg to about 900 mg (eg, about 800 mg) of anti-LAG-3 antibody molecule (eg, anti-LAG-3 antibody molecule as described herein). In some embodiments, the composition or formulation is administered or used once every 3 weeks or once every 4 weeks. In some embodiments, the composition or agent comprises about 400 mg of an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule as described herein), and is administered or used once every three weeks do. In some embodiments, the composition or formulation comprises about 533 mg or 600 mg of anti-LAG-3 antibody molecule (e.g., anti-LAG-3 antibody molecule as described herein), once every 4 weeks Administered or used. In some embodiments, the composition or agent comprises about 800 mg of an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule as described herein) and is administered or used once every 4 weeks do. In certain embodiments, the composition or agent is used to treat cancer, such as cancer disclosed herein.

Additional features or embodiments of the methods, compositions, dosage formulations and kits described herein include one or more of the following:

Antibody molecule for LAG-3

In one embodiment, the anti-LAG-3 antibody molecule is from a heavy chain and a light chain variable region comprising the amino acid sequence set forth in Table 5 (e.g., the heavy chain of BAP050-clone I or BAP050-clone J disclosed in Table 5 and At least 1, 2, 3, 4, 5 or 6 complementarity determining regions (CDRs) (or collectively all CDRs) from the light chain variable region sequence) or from those encoded by the nucleotide sequences set forth in Table 5 Includes. In some embodiments, CDRs are according to the Kabat definition (eg, as shown in Table 5). In some embodiments, CDRs are according to the Chothia definition (eg, as shown in Table 5). In some embodiments, the CDRs follow the combined CDR definitions of both Kabat and Chothia (eg, as shown in Table 5). In one embodiment, the combination of the Kabat and Chothia CDRs of VH CDR1 comprises the amino acid sequence GFTLTNYGMN (SEQ ID NO: 766). In one embodiment, one or more (or collectively all CDRs) of the CDRs are 1, 2, 3, 4, 5, 6 compared to those encoded by the amino acid sequence set forth in Table 5, or the nucleotide sequence set forth in Table 5 Dog or more changes, eg, amino acid substitutions (eg, conservative amino acid substitutions) or deletions.

In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain variable region comprising the VHCDR1 amino acid sequence of SEQ ID NO: 701, the VHCDR2 amino acid sequence of SEQ ID NO: 702, and the VHCDR3 amino acid sequence of SEQ ID NO: 703 ( VH); And a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 710, the VLCDR2 amino acid sequence of SEQ ID NO: 711, and the VLCDR3 amino acid sequence of SEQ ID NO: 712, each of which is disclosed in Table 5 It is done.

In one embodiment, the anti-LAG-3 antibody molecule is VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 736 or 737, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 738 or 739, and SEQ ID NO: A VH comprising VHCDR3 encoded by the nucleotide sequence of 740 or 741; And VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 746 or 747, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 748 or 749, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 750 or 751. Including VL, each of which is disclosed in Table 5. In one embodiment, the anti-LAG-3 antibody molecule is VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 758 or 737, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 759 or 739, and SEQ ID NO: A VH comprising VHCDR3 encoded by the nucleotide sequence of 760 or 741; And VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 746 or 747, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 748 or 749, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 750 or 751. Including VL, each of which is disclosed in Table 5.

In one embodiment, the anti-LAG-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 706, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 706. Including VH. In one embodiment, the anti-LAG-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 718, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 718. Including VL. In one embodiment, the anti-LAG-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 724, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 724. Including VH. In one embodiment, the anti-LAG-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 730, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 730. Including VL. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 706 and a VL comprising the amino acid sequence of SEQ ID NO: 718. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 724 and a VL comprising the amino acid sequence of SEQ ID NO: 730.

In one embodiment, the antibody molecule is by a nucleotide sequence of SEQ ID NO: 707 or 708, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 707 or 708 Coded VH. In one embodiment, the antibody molecule is by a nucleotide sequence of SEQ ID NO: 719 or 720, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 719 or 720 Includes coded VL. In one embodiment, the antibody molecule is by a nucleotide sequence of SEQ ID NO: 725 or 726, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 725 or 726 Coded VH. In one embodiment, the antibody molecule is by a nucleotide sequence of SEQ ID NO: 731 or 732, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 731 or 732. Includes coded VL. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 707 or 708 and a VL encoded by the nucleotide sequence of SEQ ID NO: 719 or 720. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 725 or 726 and a VL encoded by the nucleotide sequence of SEQ ID NO: 731 or 732.

In one embodiment, the anti-LAG-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 709, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 709. Includes heavy chains. In one embodiment, the anti-LAG-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 721, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 721. Includes light chains. In one embodiment, the anti-LAG-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 727, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 727. Includes heavy chains. In one embodiment, the anti-LAG-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 733, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 733. Includes light chains. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 709 and a light chain comprising the amino acid sequence of SEQ ID NO: 721. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 727 and a light chain comprising the amino acid sequence of SEQ ID NO: 733.

In one embodiment, the antibody molecule is by a nucleotide sequence of SEQ ID NO: 716 or 717, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 716 or 717 Coded heavy chain. In one embodiment, the antibody molecule is by a nucleotide sequence of SEQ ID NO: 722 or 723, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 722 or 723 Coded light chain. In one embodiment, the antibody molecule is by a nucleotide sequence of SEQ ID NO: 728 or 729, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 728 or 729. Coded heavy chain. In one embodiment, the antibody molecule is by a nucleotide sequence of SEQ ID NO: 734 or 735, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 734 or 735 Coded light chain. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 716 or 717 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 722 or 723. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 728 or 729 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 734 or 735.

Other exemplary LAG-3 inhibitors

In one embodiment, the anti-LAG-3 antibody molecule is BMS-986016 (Bristol-Myers Squibb), also known as BMS986016. BMS-986016 and other anti-LAG-3 antibodies are disclosed in WO 2015/116539 and US 9,505,839, the entire contents of which are incorporated by reference. In one embodiment, the anti-LAG-3 antibody molecule comprises, for example, one or more (or collectively all CDR sequences) of the CDR sequences of BMS-986016, as disclosed in Table 6, heavy or light chain variable region sequences. , Or heavy or light chain sequences.

In one embodiment, the anti-LAG-3 antibody molecule is TSR-033 (Tesaro). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more (or collectively all CDR sequences) of the CDR sequences of TSR-033, heavy or light chain variable region sequences, or heavy or light chain sequences.

In one embodiment, the anti-LAG-3 antibody molecule is IMP731 or GSK2831781 (GSK and Prima BioMed). IMP731 and other anti-LAG-3 antibodies are disclosed in WO 2008/132601 and US 9,244,059, the entire contents of which are incorporated by reference. In one embodiment, the anti-LAG-3 antibody molecule is, for example, one or more (or collectively all CDR sequences) of the CDR sequences of IMP731 as disclosed in Table 6, heavy or light chain variable region sequences, or Heavy chain or light chain sequence. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more (or collectively all CDR sequences) of the CDR sequences of GSK2831781, heavy or light chain variable region sequences, or heavy or light chain sequences.

In one embodiment, the anti-LAG-3 antibody molecule is IMP761 (Prima Biomed). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more (or collectively all CDR sequences) of the CDR sequences of IMP761, heavy or light chain variable region sequences, or heavy or light chain sequences.

Additional known anti-LAG-3 antibodies are, for example, WO 2008/132601, WO 2010/019570, WO 2014/140180, WO 2015/116539, WO 2015/200119, WO 2016/028672, US 9,244,059, US 9,505,839, the entire contents of which are incorporated by reference.

In one embodiment, an anti-LAG-3 antibody is an antibody that competes for and / or binds to binding of one of the anti-LAG-3 antibodies described herein with the same epitope on LAG-3.

In one embodiment, the anti-LAG-3 inhibitor is a soluble LAG-3 protein, for example IMP321 (Prima Biomed), as disclosed in WO 2009/044273, incorporated herein by reference in its entirety.

Formulation

The anti-LAG-3 antibody molecule can be formulated into an agent (eg, a dosage form or dosage form) suitable for administration to a subject (eg, intravenous administration) as described herein. The formulations described herein can be liquid formulations, lyophilized formulations, or reconstituted formulations.

In certain embodiments, the formulation is a liquid formulation. In some embodiments, the formulation (eg, liquid formulation) comprises an anti-LAG-3 antibody molecule (eg, an anti-LAG-3 antibody molecule described herein) and a buffer.

In some embodiments, the formulation (e.g., liquid formulation) is 25 mg / mL to 250 mg / mL, e.g., 50 mg / mL to 200 mg / mL, 60 mg / mL to 180 mg / mL, 70 mg / mL to 150 mg / mL, 80 mg / mL to 120 mg / mL, 90 mg / mL to 110 mg / mL, 50 mg / mL to 150 mg / mL, 50 mg / mL to 100 mg / mL, 150 mg / mL to 200 mg / mL, or 100 mg / mL to 200 mg / mL, e.g. 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 anti-LAG-3 antibody molecules present at concentrations of mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, or 150 mg / mL. In certain embodiments, the anti-LAG-3 antibody molecule is present at a concentration of 80 mg / mL to 120 mg / mL, for example 100 mg / mL.

In some embodiments, the formulation (eg, liquid formulation) comprises a buffer that includes histidine (eg, histidine buffer). In certain embodiments, the buffer (e.g., histidine buffer) is 1 mM to 100 mM, e.g., 2 mM to 50 mM, 5 mM to 40 mM, 10 mM to 30 mM, 15 to 25 mM, 5 mM To 40 mM, 5 mM to 30 mM, 5 mM to 20 mM, 5 mM to 10 mM, 40 mM to 50 mM, 30 mM to 50 mM, 20 mM to 50 mM, 10 mM to 50 mM, or 5 mM to Present at a concentration of 50 mM, eg 2 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, or 50 mM. In some embodiments, the buffer (eg, histidine buffer) is present at a concentration of 15 mM to 25 mM, eg, 20 mM. In other embodiments, the buffer (eg, histidine buffer) or formulation has a pH of 4 to 7, eg, 5 to 6, eg, 5, 5.5, or 6. In some embodiments, the buffer (eg, histidine buffer) or formulation has a pH of 5-6, eg 5.5. In certain embodiments, the buffer comprises a histidine buffer at a concentration of 15 mM to 25 mM (eg, 20 mM) and has a pH of 5 to 6 (eg, 5.5). In certain embodiments, the buffering agent includes histidine and histidine-HCl.

In some embodiments, the formulation (eg, liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 80 to 120 mg / mL, eg, 100 mg / mL; And a buffer comprising histidine buffer at a concentration of 15 mM to 25 mM (eg, 20 mM) (pH 5 to 6 (eg, 5.5)).

In some embodiments, the formulation (eg, liquid formulation) further comprises carbohydrates. In certain embodiments, the carbohydrate is sucrose. In some embodiments, the carbohydrate (eg, sucrose) is 50 mM to 500 mM, eg, 100 mM to 400 mM, 150 mM to 300 mM, 180 mM to 250 mM, 200 mM to 240 mM, 210 mM to 230 mM, 100 mM to 300 mM, 100 mM to 250 mM, 100 mM to 200 mM, 100 mM to 150 mM, 300 mM to 400 mM, 200 mM to 400 mM, or 100 mM to 400 mM, e.g. For example, it is present at a concentration of 100 mM, 150 mM, 180 mM, 200 mM, 220 mM, 250 mM, 300 mM, 350 mM, or 400 mM. In some embodiments, the formulation comprises carbohydrate or sucrose present at a concentration of 200 mM to 250 mM, eg, 220 mM.

In some embodiments, the formulation (eg, liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 80 to 120 mg / mL, eg, 100 mg / mL; A buffer comprising a histidine buffer at a concentration of 15 mM to 25 mM (eg, 20 mM); And carbohydrates or sucrose (pH 5-6 (eg 5.5)) present at a concentration of 200 mM to 250 mM, eg 220 mM.

In some embodiments, the formulation (eg, liquid formulation) further comprises a surfactant. In certain embodiments, the surfactant is polysorbate 20. In some embodiments, the surfactant or polysorbate 20 is 0.005% to 0.1% (w / w), e.g., 0.01% to 0.08%, 0.02% to 0.06%, 0.03% to 0.05%, 0.01% to 0.06 %, 0.01% to 0.05%, 0.01% to 0.03%, 0.06% to 0.08%, 0.04% to 0.08%, or 0.02% to 0.08% (w / w), e.g., 0.01%, 0.02%, 0.03% , 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1% (w / w). In some embodiments, the formulation comprises surfactant or polysorbate 20 present at a concentration of 0.03% to 0.05%, for example 0.04% (w / w).

In some embodiments, the formulation (eg, liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 80 to 120 mg / mL, eg, 100 mg / mL; A buffer comprising a histidine buffer at a concentration of 15 mM to 25 mM (eg, 20 mM); Carbohydrate or sucrose present at a concentration of 200 mM to 250 mM, eg, 220 mM; And surfactant or polysorbate 20 (pH 5-6 (eg 5.5)) present at a concentration of 0.03% to 0.05%, for example 0.04% (w / w).

In some embodiments, the formulation (eg, liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 100 mg / mL; A buffer comprising a histidine buffer at a concentration of 20 mM (eg, histidine / histidine-HCL); Carbohydrate or sucrose present at a concentration of 220 mM; And surfactant or polysorbate 20 (pH 5-6 (eg 5.5)) present at a concentration of 0.04% (w / w).

The formulations described herein can be stored in containers. Containers used for any of the formulations described herein can include, for example, vials, and optionally stoppers, caps, or both. In certain embodiments, the vial is a glass vial, for example a 6R white glass vial. In other embodiments, the stopper is a rubber stopper, for example a gray rubber stopper. In other embodiments, the cap is a flip-off cap, such as an aluminum flip-off cap. In some embodiments, the container includes a 6R white glass vial, a gray rubber stopper and an aluminum flip-off cap. In some embodiments, a container (eg, vial) is a container for single-use. In certain embodiments, 25 mg / mL to 250 mg / mL, for example 50 mg / mL to 200 mg / mL, 60 mg / mL to 180 mg / mL, 70 mg / mL to 150 mg / mL, 80 mg / mL to 120 mg / mL, 90 mg / mL to 110 mg / mL, 50 mg / mL to 150 mg / mL, 50 mg / mL to 100 mg / mL, 150 mg / mL to 200 mg / mL, or 100 mg / mL to 200 mg / mL, e.g. 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 An anti-LAG-3 antibody molecule at mg / mL, 130 mg / mL, 140 mg / mL, or 150 mg / mL is present in a container (eg, a vial).

In another aspect, the disclosure features a treatment kit comprising an anti-LAG-3 antibody molecule, composition, or formulation described herein, and instructions for use according to, for example, a dosing regimen described herein.

Therapeutic use

The anti-LAG-3 antibody molecules described herein can inhibit, reduce or neutralize one or more activities of LAG-3, resulting in blocking or reducing immune checkpoints. Thus, the anti-LAG-3 antibody molecules described herein can be used to treat or prevent disorders (e.g., cancer) where it is desirable to enhance the immune response in a subject.

Thus, in another aspect, a method of modulating an immune response in a subject is provided. The method comprises administering to a subject an anti-LAG-3 antibody molecule disclosed herein, alone or in combination with one or more therapeutic agents, procedures, or modalities, according to the dosing regimen described herein, such that the immune response in the subject is modulated. Includes. In one embodiment, the antibody molecule can enhance, stimulate or increase the immune response in the subject. The subject can be a mammal, such as a primate, preferably a higher primate, such as a human (eg, a patient with or at risk of having a disorder described herein). In one embodiment, the subject needs an enhancement of the immune response. In one embodiment, the subject has or is at risk of having a disorder as described herein, eg, a cancer or infectious disorder as described herein. In certain embodiments, the subject is or is at risk of being immunocompromised. For example, the subject is or has been receiving chemotherapy treatment and / or radiation therapy. Alternatively or in combination, the subject is at risk of being immunocompromised or immunocompromised as a result of the infection.

In one aspect, a method of treating a cancer or tumor in a subject (eg, one or more of reducing, inhibiting or delaying progression) is provided. Methods include administering to a subject an anti-LAG-3 antibody molecule described herein, alone or in combination with one or more therapeutic agents, procedures, or modalities, according to the dosing regimen described herein.

In certain embodiments, cancers treated with anti-LAG-3 antibody molecules include, but are not limited to, solid tumors, hematologic cancers (e.g., leukemia, lymphoma, myeloma, e.g. multiple myeloma), and metastatic lesions. It does not work. In one embodiment, the cancer is a solid tumor. Examples of solid tumors include malignancies of various organ systems, such as sarcomas and carcinomas, such as adenocarcinomas such as lung, breast, ovary, lymphoid, gastrointestinal (e.g. colon), anus, genital and genitourinary tracts ( For example, affecting the kidneys, urinary tract epithelium, bladder cells, prostate), pharynx, CNS (e.g. brain, nerve or glial cells), head and neck, skin (e.g. melanoma), and pancreas , As well as malignancies such as colon cancer, rectal cancer, renal cancer (e.g. renal cell carcinoma (transparent or non-transparent cell renal cell carcinoma)), liver cancer, lung cancer (e.g., non-small cell lung cancer (squamous or non-squamous) Non-small cell lung cancer)), small intestine cancer and adenocarcinoma including esophageal cancer.The cancer can be early, middle, late or metastatic cancer.

In one embodiment, the cancer is lung cancer (eg, non-small cell lung cancer (NSCLC) (eg, NSCLC with squamous and / or non-squamous histology, or NSCLC adenocarcinoma), or small cell lung cancer (SCLC)), skin cancer (E.g., Merkel cell carcinoma or melanoma (e.g., advanced melanoma)), ovarian cancer, mesothelioma, bladder cancer, soft tissue sarcoma (e.g., periplasmic cell tumor (HPC)), bone cancer (bone sarcoma) , Kidney cancer (e.g. renal cancer (e.g. renal cell carcinoma)), liver cancer (e.g. hepatocellular carcinoma), cholangiocarcinoma, sarcoma, myelodysplastic syndrome (MDS), prostate cancer, breast cancer (e.g. For example, breast cancer that does not express one, two, or both of estrogen receptors, progesterone receptors, or Her2 / neu, such as triple negative breast cancer), colorectal cancer, nasopharyngeal cancer, duodenal cancer, endometrial cancer, pancreatic cancer, two Cervical cancer (eg, head and neck squamous cell carcinoma (HNSCC), anal cancer, gastro-esophageal cancer, thyroid Cancer (eg, anaplastic thyroid carcinoma), cervical cancer, neuroendocrine tumor (NET) (eg, atypical lung carcinoid tumor), lymphoproliferative disease (eg, post-transplant lymphoproliferative disease) , Lymphoma (e.g. T-cell lymphoma, B-cell lymphoma or non-Hodgkin's lymphoma), myeloma (e.g. multiple myeloma), or leukemia (e.g. myelogenous leukemia or lymphoid leukemia) do.

In certain embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a brain tumor, eg, a glioblastoma, neuroeducation, or recurrent brain tumor. In some embodiments, the cancer is pancreatic cancer, eg, advanced pancreatic cancer. In some embodiments, the cancer is skin cancer, such as melanoma (eg, stage II-IV melanoma, HLA-A2 positive melanoma, unresectable melanoma, or metastatic melanoma), or Merkel cell carcinoma. . In some embodiments, the cancer is renal cancer, eg, renal cell carcinoma (RCC) (eg, metastatic renal cell carcinoma). In some embodiments, the cancer is breast cancer, eg, metastatic breast carcinoma or stage IV breast carcinoma, such as triple negative breast cancer (TNBC). In some embodiments, the cancer is a virus-associated cancer. In some embodiments, the cancer is anal canal cancer (eg, squamous cell carcinoma of the anal canal). In some embodiments, the cancer is cervical cancer (eg, squamous cell carcinoma of the cervix). In some embodiments, the cancer is gastric cancer (eg, Epstein Barr virus (EBV) positive gastric cancer or gastric or gastro-esophageal junction carcinoma). In some embodiments, the cancer is head and neck cancer (eg, HPV positive and negative squamous cell head and neck cancer (SCCHN)). In some embodiments, the cancer is nasopharyngeal cancer (NPC). In some embodiments, the cancer is penile cancer (eg, squamous cell carcinoma of the penis). In some embodiments, the cancer is vaginal or vulvar cancer (eg, squamous cell carcinoma of the vagina or vulva). In some embodiments, the cancer is colorectal cancer, e.g., recurrent colorectal cancer or metastatic colorectal cancer, e.g., microsatellite unstable colorectal cancer, microsatellite stable colorectal cancer, mismatch recovery proficient colorectal cancer, or mismatch repair Deficient colorectal cancer. In some embodiments, the cancer is lung cancer, eg, non-small cell lung cancer (NSCLC).

In certain embodiments, the cancer is blood cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is a lymphoma, such as Hodgkin's lymphoma (HL) or diffuse versus B cell lymphoma (DLBCL) (eg, recurrent or refractory HL or DLBCL). In some embodiments, the cancer is myeloma.

In another embodiment, the cancer is selected from carcinoma (eg, advanced or metastatic carcinoma), melanoma or lung carcinoma, such as non-small cell lung carcinoma. In one embodiment, the cancer is lung cancer, such as non-small cell lung cancer or small cell lung cancer. In some embodiments, the non-small cell lung cancer is stage I (eg, Ia or Ib stage), stage II (eg, IIa or IIb stage), stage III (eg, IIIa or IIIb stage), or IV Is non-small cell lung cancer. In one embodiment, the cancer is melanoma, eg, advanced melanoma. In one embodiment, the cancer is advanced or nonresectable melanoma that does not respond to other therapies. In other embodiments, the cancer is melanoma with a BRAF mutation (eg, BRAF V600 mutation). In another embodiment, the cancer is a viral infection, e.g., hepatocarcinoma with or without chronic viral hepatitis, e.g., advanced hepatocarcinoma. In another embodiment, the cancer is prostate cancer, eg, advanced prostate cancer. In another embodiment, the cancer is myeloma, for example multiple myeloma. In another embodiment, the cancer is renal cancer, such as renal cell carcinoma (RCC) (eg, metastatic RCC, non-transparent cell renal cell carcinoma (nccRCC), or clear cell renal cell carcinoma (CCRCC)).

In one embodiment, the cancer microenvironment has elevated levels of LAG-3 expression. In one embodiment, the cancer microenvironment has an elevated level of PD-L1 expression. Alternatively or in combination, the cancer microenvironment may have increased IFNγ and / or CD8 expression.

In some embodiments, the subject has a high PD-L1 level or one or more of expression, or a tumor that is tumor infiltrating lymphocyte (TIL) + (eg, with an increased number of TILs), or both. Or is confirmed to have. In certain embodiments, the subject has or is confirmed to have a tumor that has high PD-L1 level or expression and is TIL +. In some embodiments, the methods described herein further include identifying the subject based on whether the tumor has a high PD-L1 level or one or more of expression, or is TIL +, or both. In certain embodiments, the methods described herein further comprise identifying the subject based on whether the tumor has a high PD-L1 level or expression and is TIL +. In some embodiments, tumors that are TIL + are positive for CD8 and IFNγ. In some embodiments, the subject has or is found to have a high percentage of cells positive for 1, 2 or more of PD-L1, CD8 and / or IFNγ. In certain embodiments, the subject has or is found to have a high percentage of cells positive for all of PD-L1, CD8 and IFNγ.

In some embodiments, the methods described herein further comprise identifying the subject based on having a high percentage of cells positive for 1, 2 or more of PD-L1, CD8 and / or IFNγ. In certain embodiments, the methods described herein further comprise identifying the subject based on having a high percentage of cells positive for all of PD-L1, CD8 and IFNγ. In some embodiments, the subject has 1, 2 or more of PD-L1, CD8 and / or IFNγ, and lung cancer, eg squamous cell lung cancer or lung adenocarcinoma (eg, NSCLC); Head and neck cancer; Squamous cell cervical cancer; Stomach cancer; Esophageal cancer; Thyroid cancer (eg, anaplastic thyroid carcinoma); Skin cancer (eg, Merkel cell carcinoma or melanoma), breast cancer (eg, TNBC), and / or nasopharyngeal cancer (NPC). In certain embodiments, the methods described herein include one, two or more of PD-L1, CD8 and / or IFNγ, and lung cancer, such as squamous cell lung cancer or lung adenocarcinoma (eg, NSCLC); Head and neck cancer; Squamous cell cervical cancer; Stomach cancer; Thyroid cancer (eg, anaplastic thyroid carcinoma); It is further described to identify the subject based on having one or more of skin cancer (e.g., Merkel cell carcinoma or melanoma), neuroendocrine tumor, breast cancer (e.g., TNBC), and / or nasopharyngeal cancer. .

The methods, compositions, and formulations disclosed herein are useful for treating metastatic lesions associated with the aforementioned cancers.

In a further aspect, the disclosure treats an infectious disease (eg, an infectious disease described herein) in a subject, comprising administering to the subject an anti-LAG-3 antibody molecule described herein according to the dosing regimen described herein. How to do.

Additionally, the present invention provides the subject with (i) an antigen so that the immune response to the antigen is enhanced in the subject; And (ii) administering an anti-LAG-3 antibody molecule described herein according to the dosing regimen described herein. The antigen can be, for example, a tumor antigen, a viral antigen, a bacterial antigen or an antigen from a pathogen.

Anti-LAG-3 antibody molecules described herein can be administered to a subject systemically (e.g., orally, parenterally, subcutaneously, intravenously, rectalally, intramuscularly, intraperitoneally, intranasally, transdermally, or inhaled). By intrathecal installation), topically, or by application to mucous membranes, such as nasal, throat and bronchial tubes. In certain embodiments, the anti-LAG-3 antibody molecule is administered intravenously at the uniform doses described herein.

Combination therapy

The anti-LAG-3 antibody molecules described herein can be used in combination with other therapeutic agents, procedures or modalities.

In one embodiment, the methods described herein include administering to a subject a combination comprising an anti-LAG-3 antibody molecule described herein in combination with an amount, therapeutic agent, procedure or modality effective to treat or prevent the disorder. do. In certain embodiments, the anti-LAG-3 antibody molecule is administered or used according to the dosing regimen described herein. In other embodiments, the antibody molecule is administered or used as a composition or formulation described herein.

The anti-LAG-3 antibody molecule and therapeutic agent, procedure or modality can be administered or used simultaneously or sequentially in any order. Any combination and sequence of anti-LAG-3 antibody molecules and therapeutic agents, procedures, or modalities (eg, as described herein) can be used. Antibody molecules and / or therapeutic agents, procedures or modalities may be administered or used during periods of active disorder, or during periods of palliative or less active disease. The antibody molecule can be administered prior to, in conjunction with, or after treatment by a therapeutic agent, procedure or modality.

In certain embodiments, the anti-LAG-3 antibody molecules described herein are other antibody molecules, chemotherapy, other anti-cancer therapies (e.g., targeted anti-cancer therapy, gene therapy, virus therapy, RNA therapy bone marrow transplantation, nanotherapy or Oncolytic drugs), cytotoxic agents, immuno-based therapies (eg cytokines or cell-based immunotherapy), surgical procedures (eg massectomy or mastectomy) or radiation procedures, or any of the above It is administered in combination with one or more of the combinations. Additional therapies may be in the form of adjuvant or neoadjuvant therapies. In some embodiments, the additional therapy is an enzymatic inhibitor (eg, a small molecule enzymatic inhibitor) or a metastatic inhibitor. Exemplary cytotoxic agents that can be administered in combination can interfere with antimicrobial agents, topoisomerase inhibitors, anti-metabolites, mitotic inhibitors, alkylating agents, anthracyclines, vinca alkaloids, inserts, signal transduction pathways. Agents, agents that promote apoptosis, proteasome inhibitors, and radiation (eg, local or systemic irradiation (eg, gamma irradiation)). In other embodiments, the additional therapy is surgery or radiation or a combination thereof. In other embodiments, the additional therapy is a therapy targeting one or more of the PI3K / AKT / mTOR pathways, HSP90 inhibitors, or tubulin inhibitors.

Alternatively, or in combination with the combination, the anti-LAG-3 antibodies described herein can be administered or used in combination with one or more of the following: immunomodulators (eg, activators or inhibition of costimulatory molecules) Inhibitors of molecules, such as inhibitors of immune checkpoint molecules); Vaccines, such as therapeutic cancer vaccines; Or other forms of cellular immunotherapy.

In certain embodiments, the anti-LAG-3 molecules described herein are administered or used in combination with modulators of costimulatory molecules or inhibitory molecules, such as co-inhibiting ligands or receptors.

In one embodiment, the anti-LAG-3 antibody molecule described herein is administered or used in combination with a modulator of a costimulatory molecule, such as an agonist. In one embodiment, the agonist of a costimulatory molecule is OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40 , BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or agonist of CD83 ligand (eg, agonistic antibody or antigen-binding fragment thereof, or soluble fusion).

In another embodiment, the anti-LAG-3 antibody molecule described herein is administered or used in combination with a GITR agonist, eg, an anti-GITR antibody molecule.

In one embodiment, the anti-LAG-3 antibody molecule described herein is PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM (e.g., CEACAM-1, CEACAM-3, and / or CEACAM-5), VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or TGF beta are administered or used in combination with inhibitors of inhibitory (or immune checkpoint) molecules. In one embodiment, the inhibitor is a soluble ligand (eg, CTLA-4-Ig), or an antibody or antibody fragment that binds PD-1, LAG-3, PD-L1, PD-L2, or CTLA-4. .

In another embodiment, the anti-LAG-3 antibody molecules described herein are administered or used in combination with a PD-1 inhibitor, eg, an anti-PD-1 antibody molecule. In another embodiment, the anti-LAG-3 antibody molecule described herein is administered or used in combination with a TIM-3 inhibitor, eg, an anti-TIM-3 antibody molecule. In another embodiment, the anti-LAG-3 antibody molecule described herein is administered or used in combination with a PD-L1 inhibitor, eg, an anti-PD-L1 antibody molecule.

In another embodiment, the anti-LAG-3 antibody molecules described herein are administered or used in combination with a chemotherapeutic agent. In certain embodiments, the chemotherapeutic agent includes a platinum agent (eg, carboplatin, cisplatin, oxaliplatin, or tetraplatin). In certain embodiments, the chemotherapeutic agent includes cisplatin, pemetrexed, or both. Cisplatin is also known as cisplatinum, platamine, neoplatin, cismaplat or cis-diammine dichlorido platinum (II) (CDDP). Pemetrexed is also (S) -2- (4- (2- (2-amino-4-oxo-4,7-dihydro-3H-pyrrolo [2,3-d] pyrimidin-5-yl ) Ethyl) benzamido) pentanedioic acid. In certain embodiments, the chemotherapeutic agent is a nucleotide analog or precursor analog (e.g., capecitabine, azacytidine, azathioprine, cytarabine, doxyfluridine, fluorouracil, gemcitabine, hydroxyurea, Mercaptopurine, methotrexate or thioguanine (thioguanine)). In certain embodiments, the chemotherapeutic agent includes a hypomethylating agent (eg, decitabine). In one embodiment, the chemotherapeutic agent comprises nab-paclitaxel.

Other exemplary chemotherapeutic agents that can be used in combination with an anti-LAG-3 antibody molecule are alkylating agents (e.g., bifunctional alkylating agents (e.g. cyclophosphamide, mechlorethamine, chlorambucil, or mel) Palan)), monofunctional alkylating agents (e.g., dacarbazine (DTIC), nitrosourea, or temozolomide (oral dacarbazine)), anthracyclines (e.g., daunorubicin, doxorubicin, epirubicin) , Idarubicin, mitoxantrone, or valubicin), cytoskeleton disruptors or taxanes (e.g., paclitaxel, docetaxel, abraxane, or taxotere), epothilone, histone deacetylase inhibitors (e.g., Vorinostat or lomidepsin), an inhibitor of topoisomerase I (e.g., irinotecan or topotecan), an inhibitor of topoisomerase II (e.g., etoposide, teniposide, or tarflupo) Seed), kinase inhibitors ( For example, bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, or bismodibib), peptide antibiotics (e.g. bleomycin or actinomycin), retinoids (e.g. tretinoin, ali Tretinoin, or bexarotene), or vinca alkaloids or derivatives thereof (eg, vinblastine, vincristine, vindesine, or vinorelbine).

In another embodiment, the anti-LAG-3 antibody molecules described herein are PD-1 inhibitors (eg, anti-PD-1 antibody molecules) and TIM-3 inhibitors (eg, anti-TIM-3 antibodies) Molecule). In another embodiment, the anti-LAG-3 antibody molecules described herein are PD-1 inhibitors (eg, anti-PD-1 antibody molecules) and PD-L1 inhibitors (eg, anti-PD-L1 antibodies) Molecule). In another embodiment, the anti-LAG-3 antibody molecules described herein are TIM-3 inhibitors (eg, anti-TIM-3 antibody molecules) and PD-L1 inhibitors (eg, anti-PD-L1 antibodies) Molecule). In another embodiment, an anti-LAG-3 antibody molecule described herein is a PD-1 inhibitor (eg, an anti-PD-1 antibody molecule) and a chemotherapeutic agent (eg, a platinum agent (eg, Carboplatin, cisplatin, oxaliplatin, or tetraplatin) or nucleotide analogs or precursor analogs (eg, capecitabine)) are administered or used in combination. In another embodiment, an anti-LAG-3 antibody molecule described herein is a CEACAM inhibitor (e.g., CEACAM-1, CEACAM-3, and / or CEACAM-5 inhibitor), e.g., an anti-CEACAM antibody molecule It is administered or used in combination with. In another embodiment, the anti-LAG-3 antibody molecule is administered or used in combination with a CEACAM-1 inhibitor, eg, an anti-CEACAM-1 antibody molecule. In another embodiment, the anti-LAG-3 antibody molecule is administered or used in combination with a CEACAM-3 inhibitor, eg, an anti-CEACAM-3 antibody molecule. In another embodiment, the anti-LAG-3 antibody molecule is administered or used in combination with a CEACAM-5 inhibitor, eg, an anti-CEACAM-5 antibody molecule.

Combinations of antibody molecules disclosed herein can be administered individually, eg, as individual antibody molecules, or linked, eg, as bispecific or trispecific antibody molecules. In one embodiment, an anti-LAG-3 antibody molecule and anti-PD-1, anti-CEACAM (eg, anti-CEACAM-1, CEACAM-3, and / or anti-CEACAM-5), anti-PD -L1, or a bispecific antibody comprising an anti-TIM-3 antibody molecule is administered. In certain embodiments, combinations of the antibodies disclosed herein are used to treat cancer, eg, cancer as described herein (eg, solid tumors or hematologic malignancy).

In another embodiment, the anti-LAG-3 antibody molecule is, for example, brain cancer (eg, glioblastoma), melanoma, renal cancer (eg, renal cell carcinoma), virus-associated cancer (eg , To treat anal duct cancer, cervical cancer, stomach cancer, head and neck cancer, nasopharyngeal cancer (NPC), penile cancer, or vaginal or vulvar cancer), colorectal cancer, or lung cancer (e.g., non-small cell lung cancer (NSCLC)), It is administered or used in combination with an anti-PD-1 antibody molecule. In certain embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with an anti-PD-1 antibody molecule, for example to treat breast cancer, such as triple negative breast cancer (TNBC).

In another embodiment, the anti-LAG-3 antibody molecule is administered or used in combination with a chemotherapeutic agent (eg, gemcitabine, paclitaxel), for example to treat pancreatic cancer or breast cancer.

In another embodiment, the anti-LAG-3 antibody molecule is a chemotherapeutic agent (e.g., a platinum agent (e.g. carboplatin, cisplatin, e.g., for treating breast cancer, e.g. TNBC), e.g. Oxaliplatin, or tetraplatin) or nucleotide analogs or precursor analogs (eg, capecitabine)) are administered or used in combination. In certain embodiments, the anti-LAG-3 antibody molecule is an anti-PD-1 antibody molecule and a chemotherapeutic agent (e.g., a platinum agent (e.g. , Carboplatin, cisplatin, oxaliplatin, or tetraplatin) or nucleotide analogs or precursor analogs (eg, capecitabine)). In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with cytokines. Cytokines can be administered as fusion molecules to anti-LAG-3 antibody molecules, or as separate compositions. In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with 1, 2, 3 or more cytokines, for example as a fusion molecule or as a separate composition. In one embodiment, the cytokine is an interleukin (IL) selected from 1, 2, 3 or more of IL-1, IL-2, IL-12, IL-15 or IL-21. In one embodiment, the bispecific antibody molecule has a first binding specificity to a first target (eg, LAG-3), a second target (eg, PD-1, TIM-3, or PD-L1) ) With a second binding specificity, and is optionally linked to an interleukin (e.g., IL-12) domain, e.g., full length IL-12 or a portion thereof. In certain embodiments, combinations of anti-LAG-3 antibody molecules and cytokines described herein are used to treat cancer, eg, cancer (eg, solid tumors) as described herein.

In other embodiments, the anti-LAG-3 antibody molecule is an antibody specific for HLA C, such as an antibody specific for killer-cell immunoglobulin-like receptors (also referred to herein as “anti-KIR antibodies”). Combination). In certain embodiments, a combination of an anti-LAG-3 antibody molecule and an anti-KIR antibody is used to treat cancer, e.g., cancer as described herein (e.g., solid tumors, e.g., advanced solid tumors). Is used.

In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with cellular immunotherapy (e.g., PROVENGE®) (e.g., sipuleucel-T)), optionally cyclophospha It is administered or used in combination with mead. In certain embodiments, a combination of an anti-LAG-3 antibody molecule, Provenge® and / or cyclophosphamide is cancer, e.g., a cancer as described herein (e.g., prostate cancer, e.g., advanced prostate Cancer).

In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with a vaccine, such as a cancer vaccine (eg, dendritic cell renal carcinoma (DC-RCC) vaccine). In one embodiment, the vaccine is peptide-based, DNA-based, RNA-based, or antigen-based, or a combination thereof. In an embodiment, the vaccine comprises one or more peptides, nucleic acids (eg, DNA or RNA), antigens, or combinations thereof. In certain embodiments, the combination of the anti-TIM-3 antibody molecule and the DC-RCC vaccine is cancer, such as cancer as described herein (e.g., renal carcinoma, e.g., metastatic renal cell carcinoma (RCC) or Used to treat clear cell renal cell carcinoma (CCRCC).

In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with an adjuvant.

In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with chemotherapy and / or immunotherapy. For example, anti-LAG-3 antibody molecules can be used alone or in combination with one or more of the following to treat myeloma: chemotherapy or other anti-cancer agents (e.g. thalidomide analogs, e.g. Lenalidomide), anti-PD-1 antibody molecules, tumor antigen-pulse dendritic cells, fusion of tumor cells and dendritic cells (e.g., electrofusion), or immunoglobulin idiota produced by malignant plasma cells Vaccination using the mouth. In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with an anti-PD-1 antibody molecule to treat myeloma, such as multiple myeloma.

In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with chemotherapy to treat lung cancer, such as non-small cell lung cancer. In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with standard lung, eg, NSCLC, chemotherapy, eg platinum dual therapy, to treat lung cancer. In another embodiment, the anti-LAG-3 antibody molecule is an indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibitor in subjects with advanced or metastatic cancer (e.g., patients with metastatic and recurrent NSCL cancer). (Eg, (4E) -4-[(3-chloro-4-fluoroanilino) -nitrosomethylidene] -1,2,5-oxadiazole-3-amine (also known as INCB24360 ), Indoxymod (1-methyl-D-tryptophan), α-cyclohexyl-5H-imidazo [5,1-a] isoindole-5-ethanol (also known as NLG919), etc. Or used.

In another embodiment, in another embodiment, the anti-LAG-3 antibody molecule is administered or used in combination with one or more of the following: an immune-based strategy (eg, interleukin-2 or interferon-α), Targeting agents (eg, VEGF inhibitors, such as monoclonal antibodies to VEGF); VEGF tyrosine kinase inhibitors such as sunitinib, sorafenib, axitinib and pazopanib; RNAi inhibitors; Or inhibitors of downstream mediators of VEGF signaling, eg inhibitors of the mammalian rapamycin target (mTOR), eg everolimus and temsirolimus. Any of the above combinations may be renal cancer, e.g. renal cell carcinoma (RCC) (e.g., clear cell renal cell carcinoma (CCRCC) or non-transparent cell renal cell carcinoma (nccRCC)) or metastatic RCC, or liver cancer (e.g. For example, hepatocellular carcinoma).

In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with a MEK inhibitor (eg, a MEK inhibitor as described herein). In some embodiments, a combination of an anti-LAG-3 antibody molecule and a MEK inhibitor is used to treat cancer (eg, cancer described herein). In some embodiments, the cancer treated in combination is selected from melanoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, hematologic malignancy or renal cell carcinoma. In certain embodiments, the cancer comprises a BRAF mutation (eg, BRAF V600E mutation), a BRAF wild type, a KRAS wild type or an activated KRAS mutation. Cancer can be early, middle or late.

In other embodiments, the anti-LAG-3 antibody molecule is a chemotherapeutic agent (e.g., a platinum agent (e.g. carboplatin, oxaliplatin, cisplatin, or tetraplatin)) or a nucleotide analog or precursor analog (e.g. For example, capecitabine)), leucovorin or 5-FU, or administered in combination with one, two or both (eg, polox co-treatment). Alternatively or in combination, the combination further comprises a VEGF inhibitor (eg, a VEGF inhibitor as disclosed herein). In some embodiments, combinations of anti-LAG-3 antibody molecules, polox co-treatment, and VEGF inhibitors are used to treat cancer (eg, cancer described herein). In some embodiments, the cancer treated in combination is selected from melanoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, hematologic malignancy or renal cell carcinoma. Cancer can be early, middle or late.

In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with a tyrosine kinase inhibitor (eg, axitinib) to treat renal cell carcinoma and other solid tumors.

In other embodiments, the anti-LAG-3 antibody molecule is combined with a 4-1BB receptor targeting agent (e.g., an antibody that stimulates signaling through 4-1BB (CD-137), e.g. PF-2566). Administered or used. In other embodiments, the anti-TIM-3 antibody molecule is administered or used in combination with a tyrosine kinase inhibitor (eg, axitinib) and a 4-1BB receptor targeting agent.

Anti-LAG-3 antibody molecules can be substances, such as cytotoxic agents or moieties (e.g., therapeutic drugs; radiation-emitting compounds; molecules of plant, fungal, or bacterial origin; or biological proteins (e.g., proteins Toxins) or particles (eg, via recombinant viral particles, eg via viral coat proteins), for example, the antibody is a radioactive isotope, such as α-, β-, or γ-releasing Sieve, or β- and γ-emitters.

Immunomodulators

The anti-LAG-3 antibody molecules described herein can be used in combination with one or more immunomodulators.

In certain embodiments, the immunomodulator is an inhibitor of the immune checkpoint molecule. In one embodiment, the immunomodulator is PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, CEACAM (eg, CEACAM-1, -3 and / or -5), VISTA, BTLA , TIGIT, LAIR1, CD160, 2B4 and / or inhibitor of TGF beta. In one embodiment, the inhibitor of the immune checkpoint molecule is PD-1, PD-L1, TIM-3, CEACAM (eg, CEACAM-1, -3 and / or -5), CTLA-4, or any thereof Inhibit the combination of.

Inhibition of inhibitory molecules can be performed at the DNA, RNA or protein level. In embodiments, inhibitory nucleic acids (eg, dsRNA, siRNA or shRNA) can be used to inhibit the expression of the inhibitory molecule. In other embodiments, the inhibitor of the inhibitory signal is a polypeptide that binds to the inhibitory molecule, such as a soluble ligand (eg, PD-1-Ig or CTLA-4 Ig), or an antibody molecule; For example, PD-1, PD-L1, PD-L2, CEACAM (e.g., CEACAM-1, -3 and / or -5), CTLA-4, TIM-3, VISTA, BTLA, TIGIT, LAIR1 , CD160, 2B4 and / or TGF beta, or combinations thereof.

In certain embodiments, the anti-LAG-3 antibody molecule is in the form of a bispecific or multispecific antibody molecule. In one embodiment, the bispecific antibody molecule has a first binding specificity and a second binding specificity to LAG-3, e.g. PD-1, PD-L1, CEACAM (e.g., CEACAM-1, -3 and / Or -5), TIM-3, or a second binding specificity for PD-L2. In one embodiment, the bispecific antibody molecule binds (i) PD-1 or PD-L1 (ii) and LAG-3. In another embodiment, the bispecific antibody molecule binds LAG-3 and TIM-3. In another embodiment, the bispecific antibody molecule binds LAG-3 and CEACAM (eg, CEACAM-1, -3 and / or -5). In another embodiment, the bispecific antibody molecule binds LAG-3 and CEACAM-1. In another embodiment, the bispecific antibody molecule binds LAG-3 and CEACAM-3. In another embodiment, the bispecific antibody molecule binds LAG-3 and CEACAM-5.

In other embodiments, anti-LAG-3 antibody molecules are used in combination with bispecific or multispecific antibody molecules. In another embodiment, the bispecific antibody molecule binds PD-1 or PD-L1. In another embodiment, the bispecific antibody molecule binds PD-1 and PD-L2. In another embodiment, the bispecific antibody molecule binds CEACAM (eg, CEACAM-1, -3 and / or -5) and TIM-3.

Any combination of these molecules can be combined with a first binding specificity for a multispecific antibody molecule, for example LAG-3, and PD-1, PD-L1, CEACAM (e.g., CEACAM-1, -3 and / or -5), TIM-3, or tri-specific antibodies comprising second and third binding specificities for two or more of PD-L2.

In certain embodiments, the immunomodulator is an inhibitor of PD-1, eg human PD-1. In another embodiment, the immunomodulator is an inhibitor of PD-L1, eg, human PD-L1. In one embodiment, the inhibitor of PD-1 or PD-L1 is an antibody molecule against PD-1 or PD-L1 (eg, an anti-PD-1 or anti-PD-L1 antibody molecule as described herein) to be.

The combination of a PD-1 or PD-L1 inhibitor and an anti-LAG-3 antibody molecule may further include one or more additional immunomodulators, for example TIM-3, CEACAM (e.g. CEACAM-1 , -3 and / or -5) or an inhibitor of CTLA-4. In one embodiment, the inhibitor of PD-1 or PD-L1 (eg, anti-PD-1 or PD-L1 antibody molecule) is an anti-LAG-3 antibody molecule and a TIM-3 inhibitor (eg, anti -TIM-3 antibody molecule). In another embodiment, the inhibitor of PD-1 or PD-L1 (eg, anti-PD-1 or PD-L1 antibody molecule) is an anti-LAG-3 antibody molecule and a CEACAM inhibitor (eg, CEACAM- 1, -3 and / or -5 inhibitors), eg, in combination with an anti-CEACAM antibody molecule. In another embodiment, an inhibitor of PD-1 or PD-L1 (eg, an anti-PD-1 or PD-L1 antibody molecule) is an anti-LAG-3 antibody molecule and a CEACAM-1 inhibitor (eg, Anti-CEACAM-1 antibody molecule). In another embodiment, an inhibitor of PD-1 or PD-L1 (eg, an anti-PD-1 or PD-L1 antibody molecule) is an anti-LAG-3 antibody molecule and a CEACAM-5 inhibitor (eg, Anti-CEACAM-5 antibody molecule). In another embodiment, an inhibitor of PD-1 or PD-L1 (eg, an anti-PD-1 or PD-L1 antibody molecule) is an anti-LAG-3 antibody molecule and a TIM-3 inhibitor (eg, Anti-TIM-3 antibody molecule). Immunomodulators and anti-LAG-3 antibody molecules and PD-1 inhibitors (eg PD-L2, CTLA-4, LAG-3, CEACAM (eg CEACAM-1, -3 and / or -5) , VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or other combinations of TGF beta) are also included within the invention. Any of the antibody molecules known in the art or disclosed herein can be used in this combination of inhibitors of checkpoint molecules.

In other embodiments, the immunomodulator is CEACAM (e.g., CEACAM-1, -3 and / or -5), e.g., human CEACAM (e.g., CEACAM-1, -3 and / or -5). It is an inhibitor. In one embodiment, the immunomodulator is an inhibitor of CEACAM-1, eg, human CEACAM-1. In another embodiment, the immunomodulator is an inhibitor of CEACAM-3, eg, human CEACAM-3. In another embodiment, the immunomodulator is an inhibitor of CEACAM-5, eg, human CEACAM-5. In one embodiment, the inhibitor of CEACAM (eg, CEACAM-1, -3 and / or -5) is an antibody molecule to CEACAM (eg, CEACAM-1, -3 and / or -5). Combinations of CEACAM (eg, CEACAM-1, -3 and / or -5) inhibitors and anti-LAG-3 antibody molecules may further include one or more additional immunomodulators, eg, TIM -3, PD-1, PD-L1 or CTLA-4.

In other embodiments, the immunomodulator is an inhibitor of TIM-3, eg human TIM-3. In one embodiment, the inhibitor of TIM-3 is an antibody molecule against TIM-3. The combination of a TIM-3 inhibitor and an anti-LAG-3 antibody molecule may further include one or more additional immunomodulators, eg, CEACAM (eg, CEACAM-1, -3 and / or- 5), PD-1, PD-L1 or CTLA-4.

In certain embodiments, the immunomodulatory agent used in the combinations disclosed herein (eg, in combination with a therapeutic agent selected from antigen-presenting combinations) is an activator or agonist of a costimulatory molecule. In one embodiment, the agonist of a costimulatory molecule is OX40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30 , Agonists of CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or CD83 ligands (e.g. agonistic antibodies or antigen-binding fragments thereof, or soluble fusions) do.

In other embodiments, the immunomodulator is a GITR agonist. In one embodiment, the GITR agonist is an antibody molecule against GITR. The anti-GITR antibody molecule and anti-LAG-3 antibody molecule may exist as individual antibody composition forms, or as bispecific antibody molecules. The combination of a GITR agonist and an anti-LAG-3 antibody molecule may further include one or more additional immunomodulators, e.g. PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3 and / or -5), or in combination with inhibitors of TIM-3. In some embodiments, the anti-GITR antibody molecule binds GITR and PD-1, PD-L1, CTLA-4, CEACAM (eg, CEACAM-1, -3 and / or -5), or TIM-3 It is a bispecific antibody. In other embodiments, the GITR agonist is a costimulatory molecule, e.g., OX40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137) ), CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or in combination with one or more additional activators of the CD83 ligand.

In other embodiments, the immunomodulator is an OX40 agonist. In one embodiment, the OX40 agonist is an antibody molecule against OX40. The OX40 antibody molecule and anti-LAG-3 antibody molecule can exist as individual antibody composition forms, or as bispecific antibody molecules. The combination of an OX40 agonist and an anti-LAG-3 antibody molecule may further include one or more additional immunomodulators, e.g. PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3 and / or -5), or in combination with inhibitors of TIM-3. In some embodiments, the anti-OX40 antibody molecule binds OX40 and PD-1, PD-L1, CTLA-4, CEACAM (eg, CEACAM-1, -3 and / or -5), or TIM-3 It is a bispecific antibody. In other embodiments, the OX40 agonist is another costimulatory molecule, e.g., GITR, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB ( CD137), CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or CD83 ligand.

Note that only exemplary combinations of inhibitors of checkpoint inhibitors or agonists of costimulatory molecules are provided herein. Further combinations of these agents are within the scope of the present invention.

Biomarker

In certain embodiments, any of the methods disclosed herein can determine the effectiveness of a therapy described herein (e.g., monotherapy or combination therapy) in a subject (e.g., a subject having cancer, e.g., a cancer described herein). Further comprising evaluation or monitoring. The method includes obtaining a value of effectiveness for therapy, where the value indicates the effectiveness of therapy.

In an embodiment, the value of effectiveness for therapy comprises a measurement of 1, 2, 3, 4, 5, 6, 7, 8, 9 or more (eg, all) of the following:

(i) parameters of the tumor infiltrating lymphocyte (TIL) phenotype;

(ii) parameters of the bone marrow cell population;

(iii) parameters of surface expression markers;

(iv) parameters of the biomarker of the immune response;

(v) parameters of systemic cytokine adjustment;

(vi) parameters of circulating free DNA (cfDNA);

(vii) parameters of systemic immune-modulation;

(viii) parameters of microbiome;

(ix) parameters of activation markers in circulating immune cells; or

(x) Parameters of circulating cytokines.

In some embodiments, the parameter of the TIL phenotype is hematoxylin and eosin (H & E) staining, CD8, FOXP3, CD4 or CD3 for TIL counts in a subject, e.g., a sample from a subject (e.g., a tumor sample). 1, 2, 3, 4 or more (eg, all) of levels or activity.

In some embodiments, the parameter of the bone marrow cell population comprises the level or activity of one or both of CD68 or CD163 in the subject, eg, a sample from the subject (eg, a tumor sample).

In some embodiments, the parameter of the surface expression marker is 1, 2 of TIM-3, PD-1, PD-L1, or LAG-3 in a subject, eg, a sample from a subject (eg, a tumor sample). , Three or more (eg, all) levels or activities. In certain embodiments, the level of TIM-3, PD-1, PD-L1, or LAG-3 is determined by immunohistochemistry (IHC). In certain embodiments, the level of TIM-3 is determined.

In some embodiments, the parameter of the biomarker of the immune response comprises the level or sequence of one or more nucleic acid-based markers in the subject, eg, a sample from the subject (eg, a tumor sample).

In some embodiments, the parameter of systemic cytokine adjustment is IL-18, IFN-γ, ITAC (CXCL11), IL in a subject, e.g., a sample from a subject (e.g., a blood sample, e.g., a plasma sample). 1, 2, 3, 4, 5, 6, 7, 8 or more of -6, IL-10, IL-4, IL-17, IL-15, or TGF-beta (e.g., all) Levels or activity.

In some embodiments, the parameter of cfDNA comprises the sequence or level of one or more circulating tumor DNA (cfDNA) molecules in a subject, eg, a sample from a subject (eg, a blood sample, eg, a plasma sample). do.

In some embodiments, the parameter of systemic immune-modulation is activated immune cells in a subject, eg, a sample from a subject (eg, a blood sample, eg, PBMC sample), eg, CD3-expressing cells, Phenotypic characterization of CD8-expressing cells, or both.

In some embodiments, the parameters of the microbiome include the sequence or expression level of one or more genes of the microbiome in a subject, eg, a sample from the subject (eg, a stool sample).

In some embodiments, the parameter of the activation marker in circulating immune cells is circulating CD8 +, HLA-DR + Ki67 +, T cells, IFN-γ, IL-18 in a sample (eg, a blood sample, eg, a plasma sample). , Or 1, 2, 3, 4, 5 or more (eg, all) levels or activity of CXCL11 (IFN-γ derived CCK) expressing cells.

In some embodiments, the parameter of circulating cytokines includes the level or activity of IL-6 in the subject, eg, a sample from the subject (eg, a blood sample, eg, a plasma sample).

In some embodiments of any of the methods disclosed herein, the therapy is a second inhibitor of an anti-TIM-3 antibody molecule and an immune checkpoint molecule described herein, e.g., an inhibitor of PD-1 (e.g., anti -PD-1 antibody molecule) or a combination of inhibitors of PD-L1 (eg, anti-PD-L1 antibody molecule).

In some embodiments of any of the methods disclosed herein, measurements of one or more of (i)-(x) are obtained from samples obtained from a subject. In some embodiments, the sample is selected from a tumor sample, blood sample (eg, plasma sample or PBMC sample), or stool sample.

In some embodiments of any of the methods disclosed herein, the subject is assessed before, during, or after receiving therapy.

In some embodiments of any of the methods disclosed herein, measurement of one or more of (i)-(x) assesses the profile for one or more of gene expression, flow cytometry, or protein expression.

In some embodiments of any of the methods disclosed herein, in circulating CD8 +, HLA-DR + Ki67 +, T cells, IFN-γ, IL-18, or CXCL11 (IFN-γ induced CCK) expressing cells in a subject or sample The presence of increased levels or activities of 1, 2, 3, 4, 5 or more (eg, all), and / or the presence of reduced levels or activity of IL-6 predicts a positive effect of the therapy It is an argument.

Alternatively, or in combination with the methods disclosed herein, 1, 2, 3, 4 or more of the following (eg, all) are performed corresponding to the values:

(i) administering therapy to the subject;

(ii) administering an altered dose of therapy;

(iii) changing the schedule or time course of therapy;

(iv) administering to the subject an additional agent (eg, a therapeutic agent described herein) in combination with therapy; or

(v) Subjects are treated with alternative therapy.

Additional embodiments

In certain embodiments, any of the methods disclosed herein further confirm the presence of LAG-3 in a subject or sample (e.g., a sample of a subject comprising cancer cells and / or immune cells such as TIL), And providing values for LAG-3. The method may further include comparing the LAG-3 value to a reference value, such as a control value. When the LAG-3 value is greater than a reference value, e.g., a control value, a therapeutically effective amount of an anti-LAG-3 antibody molecule described herein is administered to the subject, optionally in combination with a second therapeutic agent, procedure, or modality described herein. To treat cancer.

In other embodiments, any of the methods disclosed herein further confirm the presence of PD-L1 in a subject or sample (eg, a sample of a subject comprising cancer cells and / or immune cells such as TIL), And providing a value for PD-L1. The method may further include comparing the PD-L1 value to a reference value, such as a control value. If the PD-L1 value is greater than a reference value, e.g., a control value, a therapeutically effective amount of an anti-LAG-3 antibody molecule described herein is administered to the subject, optionally in combination with a second therapeutic agent, procedure, or modality described herein. To treat cancer.

In other embodiments, any of the methods disclosed herein are 1 of PD-L1, CD8, or IFN-γ in a subject or sample (eg, a sample of a subject comprising cancer cells and optionally immune cells such as TILs). , Confirming the presence of two or both, further comprising providing values for one, two or both of PD-L1, CD8, and IFN-γ. The method may further include comparing PD-L1, CD8, and / or IFN-γ values to a reference value, such as a control value. If the PD-L1, CD8, and / or IFN-γ values are greater than a reference value, such as a control value, a therapeutically effective amount of an anti-LAG-3 antibody molecule described herein, optionally a second therapeutic agent, procedure described herein , Or in combination with a form to administer to a subject to treat cancer.

Subjects may include cancers described herein, such as solid tumors or blood cancers, e.g. brain tumors (e.g. glioblastoma, neuroeducation, or recurrent brain tumors), pancreatic cancer (e.g. advanced pancreatic cancer), skin cancer ( For example, melanoma (eg, stage II-IV melanoma, HLA-A2 positive melanoma, unresectable melanoma or metastatic melanoma), or Merkel cell carcinoma), renal cancer (eg, renal cell carcinoma) (RCC) (e.g., metastatic renal cell carcinoma)), breast cancer (e.g., metastatic breast carcinoma or stage IV breast carcinoma, e.g., triple negative breast cancer (TNBC)), virus-associated cancer, anal canal cancer ( For example, squamous cell carcinoma of the anal canal), cervical cancer (e.g., squamous cell carcinoma of the cervix), gastric cancer (e.g. Epstein Barr virus (EBV) positive gastric cancer or gastric or gastro-esophageal junction carcinoma), Head and neck cancer (e.g. HPV positive and negative squamous cell head and neck (SCCHN)), nasopharyngeal cancer (NPC), penile cancer (e.g. squamous cell carcinoma of the penis), vaginal or vulvar cancer (e.g. squamous cell carcinoma of the vagina or vulva), colorectal cancer (e.g. Recurrent colorectal cancer or metastatic colorectal cancer, e.g. microsatellite unstable colorectal cancer, microsatellite stable colorectal cancer, mismatch recovery proficient colorectal cancer, or mismatch recovery deficient colorectal cancer), lung cancer (e.g. non-small cell lung cancer) (NSCLC)), leukemia, lymphoma (e.g. Hodgkin's lymphoma (HL) or diffuse versus B cell lymphoma (DLBCL), e.g. recurrent or refractory HL or DLBCL), myeloma, or metastatic lesions of cancer Can have

All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

Other features, objects, and advantages of the invention will be apparent from the detailed description and drawings, and from the claims.

LAG-3 (CD223) is an immune checkpoint inhibitor that binds MHC II, LSECtin, and galectin-3. LAG-3 is expressed on the surface of immune cells, including CD4 + and CD8 + T effector cells, regulatory T cells (Treg), natural killer (NK) cells, and plasmacytoid dendritic cells. LAG-3 binding has been found to negatively regulate T cell signaling and increase the inhibitory function of Treg, which is then expected to reduce T-cell activity against tumor cells. Blockade of LAG-3 has been found to activate T cells by increasing T cell proliferation and cytokine secretion (IFN-γ).

Thus, at least partially, disclosed herein are antibody molecules (eg, humanized antibody molecules) that bind LAG-3 with high affinity and specificity. Pharmaceutical compositions and dosage formulations comprising anti-LAG-3 antibody molecules are also provided. Anti-LAG-3 antibody molecules disclosed herein are used to treat or prevent disorders, such as cancerous disorders (e.g., solid tumors and blood cancers), as well as infectious diseases (e.g., chronic infectious disorders or sepsis) ( Alone or in combination with other therapeutic agents, procedures or modalities). For example, an anti-LAG-3 antibody molecule described herein can treat or prevent cancer (e.g., cancer described herein), e.g., breast cancer, e.g., triple negative breast cancer (TNBC). To the end, other therapeutic agents (e.g., PD-1 inhibitors (e.g., anti-PD-1 antibody molecules described herein) or chemotherapeutic agents (e.g., platinum agents (e.g. carboplatin, cisplatin) , Oxaliplatin, or tetraplatin) or nucleotide analogs or precursor analogs (e.g., capecitabine)). Accordingly, disclosed herein are methods, including dosing regimens, for treating various disorders using anti-LAG-3 antibody molecules. In certain embodiments, the anti-LAG-3 antibody molecule is administered or used in uniform or fixed doses.

Justice

Additional terms are defined below and throughout the application.

The singular form as used herein refers to the grammatical object of one or more (eg at least one) items.

The term “or” is used herein to mean the term “and / or” and is used interchangeably therewith, unless the context clearly indicates otherwise.

“About” and “approximately” will generally refer to the degree of tolerance for a measured quantity given the nature or accuracy of the measurement. Exemplary degrees of error are within 20 percent (%) of a given value or range of values, typically within 10%, more typically within 5%.

“Combination” or “in combination with” does not intend that the therapy or therapeutic agent be administered at the same time and / or formulated for delivery together, but these methods of delivery are within the scope described herein. The therapeutic agent in combination can be administered in combination with, before or after one or more other additional therapies or therapeutic agents. The therapeutic agent or treatment protocol can be administered in any order. Generally, each agent will be administered at a dose and / or time schedule determined for that agent. Additionally, it will be appreciated that additional therapeutic agents utilized in this combination may be administered together in a single composition or may be administered separately in different compositions. In general, it is expected that additional therapeutic agents used in combination will be used at levels not exceeding the levels when they are used individually. In some embodiments, the level used in combination will be lower than those used individually.

In an embodiment, the additional therapeutic agent is administered at a therapeutic dose or a lower dose. In certain embodiments, the concentration of the second therapeutic agent required to achieve inhibition, e.g., growth inhibition, can be adjusted when the second therapeutic agent is administered in combination with a first therapeutic agent, e.g., an anti-LAG-3 antibody molecule. 2 The treatment is lower than when administered individually. In certain embodiments, the concentration of the first therapeutic agent required to achieve inhibition, eg, growth inhibition, is lower than when the first therapeutic agent is administered separately when the first therapeutic agent is administered in combination with the second therapeutic agent. In certain embodiments, in combination therapy, the concentration of the second therapeutic agent required to achieve inhibition, e.g., growth inhibition, is lower than the therapeutic dose of the second therapeutic agent as monotherapy, e.g., 10-20%, 20- 30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80-90% lower. In certain embodiments, in combination therapy, the concentration of the first therapeutic agent required to achieve inhibition, e.g., growth inhibition, is lower than the therapeutic dose of the first therapeutic agent as monotherapy, e.g., 10-20%, 20- 30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80-90% lower.

The terms “inhibition”, “inhibitor”, or “antagonist” include specific parameters of a given molecule, eg, an immune checkpoint inhibitor, eg, reduction of activity. For example, inhibition of at least 5%, 10%, 20%, 30%, 40% or more activity, such as PD-1 or PD-L1 activity, is included in this term. Therefore, the suppression need not be 100%.

The terms “activation”, “activator”, or “agonist” include specific parameters of a given molecule, eg a costimulatory molecule, such as an increase in activity. For example, an increase in activity of at least 5%, 10%, 25%, 50%, 75% or more, such as costimulatory activity, is included in this term.

The term “anti-cancer effect” is associated with, for example, a decrease in tumor volume, a decrease in the number of cancer cells, a decrease in the number of metastases, an increase in life expectancy, a decrease in cancer cell proliferation, a decrease in cancer cell survival, or a cancerous condition. Refers to biological effects that can be exhibited by various means, including but not limited to the improvement of various physiological symptoms. The "anti-cancer effect" can also first be indicated by the ability of peptides, polynucleotides, cells and antibodies in the prevention of cancer development.

The term “anti-tumor effect” will be indicated by a variety of means, including but not limited to, for example, a reduction in tumor volume, a decrease in the number of tumor cells, a decrease in tumor cell proliferation, or a decrease in tumor cell survival. Refers to a possible biological effect.

The term "cancer" refers to a disease characterized by rapid and uncontrolled growth of abnormal cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers are described herein and include solid tumors such as lung cancer, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, renal cancer, liver cancer, and brain cancer, and blood malignancy, eg Examples include, but are not limited to, lymphoma and leukemia. The terms “tumor” and “cancer” are used interchangeably herein, for example, both terms encompass solid and liquid, eg diffuse or circulating tumors. The term "cancer" or "tumor" as used herein includes precancerous, as well as malignant cancers and tumors.

The term “antigen presenting cell” or “APC” refers to immune system cells, such as accessory cells (eg, B-cells, dendritic cells, etc.), which are complexed with a major histocompatibility complex (MHC) on their surface Foreign antigens are displayed. T-cells can recognize these complexes using their T-cell receptor (TCR). APC processes antigens and presents them to T-cells.

The term “co-stimulatory molecule” refers to a cognate binding partner on T cells that specifically binds to a costimulatory ligand and mediates a costimulatory response by T cells, such as but not limited to proliferation. The costimulatory molecule is a cell surface molecule other than the antigen receptor required for an efficient immune response or a ligand thereof. Co-stimulatory molecules include MHC class I molecules, TNF receptor proteins, immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules (SLAM proteins), activated NK cell receptors, BTLA, tall ligand receptors, OX40, CD2 , CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CD11a / CD18), 4-1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8 Alpha, CD8 Beta, IL2R Beta, IL2R Gamma, IL7R Alpha, ITGA4, VLA1, CD49a, ITGA4 , IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7 , NKG2D, NKG2C, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D) , CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76 , PAG / Cbp, CD19a, and a ligand specifically binding to CD83.

The term “immune effector cell” or “effector cell” as used herein refers to a cell involved in the promotion of an immune response, eg, an immune effector response. Examples of immune effector cells include T cells, such as alpha / beta T cells and gamma / delta T cells, B cells, natural killer (NK) cells, natural killer T (NKT) cells, mast cells and bone marrow-derived phagocytes. Includes.

As used herein, the term “immune effector” or “effector” “function” or “response” refers to a function or response, eg, of an immune effector cell, that promotes or promotes an immune attack of a target cell. For example, immune effector function or response refers to the properties of T or NK cells that promote the death of target cells, or inhibition of growth or proliferation. In the case of T cells, primary stimulation and co-stimulation are examples of immune effector function or response.

The term “effector function” refers to the specialized function of the cell. The effector function of T cells can be, for example, cytolytic activity or helper activity, including the secretion of cytokines.

As used herein, the terms “treat”, “treatment” and “treating” are disorders resulting from administration of one or more therapies, such as the progression, severity and / or duration of a proliferative disorder, or a decrease or amelioration. Or improvement of one or more symptoms of the disorder (preferably, one or more identifiable symptoms). In a specific embodiment, the terms “treat”, “treatment” and “treating” refer to at least one measurable physical parameter of a proliferative disorder that may not necessarily be discernible by the patient, such as improvement of tumor growth. do. In other embodiments, the terms “treat”, “treatment” and “treating” are physically, eg, by stabilization of identifiable symptoms, physiologically, eg, by stabilization of physical parameters, or both. Refers to the inhibition of the progression of proliferative disorders. In other embodiments, the terms “treat”, “treatment” and “treating” refer to reduction or stabilization of tumor size or number of cancerous cells.

The compositions, formulations, and methods of the present invention are directed to polypeptides and nucleic acids having a specified sequence, or a sequence substantially identical or similar thereto, e.g., at least 85%, 90%, 95% or more identical to a specified sequence. Encompasses. With respect to the amino acid sequence, the term “substantially identical” means that the first and second amino acid sequences are identical to the aligned amino acid residues in the second amino acid sequence such that the first and second amino acid sequences have a common structural domain and / or a common functional activity, or ii ) Is used herein to refer to a first amino acid that contains a sufficient number or a minimum number of amino acid residues that are conservative substitutions thereof. For example, the amino acid sequence can be at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or at least about 85%, 90%, 91%, It contains a common structural domain with 99% identity.

With regard to the nucleotide sequence, the term “substantially identical” is ordered within the second nucleic acid sequence such that the first and second nucleotide sequences encode a polypeptide having a common functional activity or a common structural polypeptide domain or a common functional polypeptide activity. It is used herein to refer to a first nucleic acid sequence containing a sufficient number or a minimum number of nucleotides equal to a nucleotide. For example, the nucleotide sequence may be at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or at least about 85%, 90%, and 96%, or a sequence provided herein. 99% identity.

The term “functional variant” refers to a polypeptide that has an amino acid sequence that is substantially identical to a naturally occurring sequence, or is encoded by a substantially identical nucleotide sequence, and that can have one or more activities of a naturally occurring sequence.

The calculation of homology or sequence identity between sequences (these terms are used interchangeably herein) is performed as follows.

To determine percent identity of two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps in one or both of the first and second amino acid or nucleic acid sequences for optimal alignment) Can be introduced, and non-homologous sequences can be ignored for comparison purposes). In a preferred embodiment, the length of the reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70 of the length of the reference sequence. %, 80%, 90%, 100%. The amino acid residues or nucleotides at the corresponding amino acid position or nucleotide position are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, the molecule is identical at that position (as used herein, the amino acid or nucleic acid "identity" is an amino acid or nucleic acid Equivalent to "homology".

Percent identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps that need to be introduced for optimal alignment of the two sequences and the length of each gap.

Comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In a preferred embodiment, the percent identity between the two amino acid sequences is Blossom 62 matrix or PAM250 matrix, and gap weights 16, 14, 12, 10, 8, 6 or 4, and length weights 1, 2, 3, 4, 5 Or using the algorithm incorporated by Needleman and Wunsch ((1970) J. Mol. Biol. 48: 444-453) into the GAP program (available at www.gcg.com) in the GCG software package using 6 Is decided. In another preferred embodiment, the percent identity between the two nucleotide sequences uses the NWSgapdna.CMP matrix, and gap weights 40, 50, 60, 70 or 80, and length weights 1, 2, 3, 4, 5 or 6 This is determined using the GAP program (available at www.gcg.com) in the GCG software package. A particularly preferred parameter set (and what should be used unless otherwise specified) is the Blossom 62 scoring matrix using Gap Penalty 12, Gap Extension Penalty 4, and Frameshift Gap Penalty 5.

Percent identity between two amino acid or nucleotide sequences was incorporated into the ALIGN program (version 2.0) using the PAM120 weighted residue table, gap length penalty 12 and gap penalty 4 [E. Meyers and W. Miller ((1989) CABIOS, 4: 11-17).

The nucleic acid and protein sequences described herein can further be used as a "query sequence" to conduct searches against public databases, for example to identify other family members or related sequences. Such searches are described in Altschul, et al. (1990) J. Mol. Biol. 215: 403-10] using the NBLAST and XBLAST programs (version 2.0). BLAST nucleotide searches can be performed with the NBLAST program, score = 100, word length = 12 to obtain nucleotide sequences homologous to the nucleic acid (SEQ ID NO: 1) molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score = 50, word length = 3 to obtain amino acid sequences homologous to protein molecules of the invention. To obtain gaped alignments for comparison purposes, Gapped BLAST was described by Altschul et al., (1997) Nucleic Acids Res. 25: 3389-3402. When using BLAST and Gapped BLAST programs, the default parameters of each program (eg, XBLAST and NBLAST) can be used. See www.ncbi.nlm.nih.gov.

As used herein, the term "hybridization under conditions of low stringency, medium stringency, high stringency, or very stringent stringency" describes conditions for hybridization and washing. Guidelines for conducting hybridization reactions are described in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6 (which is incorporated by reference). Aqueous and non-aqueous methods are described in the above references, and either can be used. The specific hybridization conditions referred to herein are as follows: 1) Low stringency hybridization conditions: 6X sodium chloride / sodium citrate (SSC) at about 45 ° C, followed by 2 washes in 0.2X SSC, 0.1% SDS at least 50 ° C ( The temperature of the washing liquid can be increased to 55 ° C. for low stringency conditions); 2) Medium stringency hybridization conditions: 6X SSC at about 45 ° C., followed by 0.2X SSC at 60 ° C., one or more washes in 0.1% SDS; 3) High stringency hybridization conditions: 6X SSC at about 45 ° C., followed by one or more washes at 65 ° C. in 0.2X SSC, 0.1% SDS; And preferably 4) Very high stringency hybridization conditions: 0.5M sodium phosphate at 65 ° C, 7% SDS, followed by one or more washes at 65 ° C in 0.2X SSC, 1% SDS. Very high stringency conditions (4) are preferred conditions and should be used unless otherwise specified.

It is understood that the molecules of the invention may have additional conservative or non-essential amino acid substitutions that have no substantial effect on their function.

The term "amino acid" is intended to encompass all molecules, whether natural or synthetic, that include both amino and acid functional groups and can be included in polymers of naturally occurring amino acids. Exemplary amino acids include naturally occurring amino acids; Analogs, derivatives and homologs thereof; Amino acid analogs with variant side chains; And all stereoisomers of any of the above. The term "amino acid" as used herein includes both D- or L- optical isomers and peptidomimetics.

“Conservative amino acid substitution” is the replacement of an amino acid residue with an amino acid residue having a similar side chain. Families of amino acid residues with similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g. lysine, arginine, histidine), amino acids with acidic side chains (e.g. aspartic acid, glutamic acid), amino acids with uncharged polar side chains (e.g. glycine , Asparagine, glutamine, serine, threonine, tyrosine, cysteine, amino acids with non-polar side chains (e.g. alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), amino acids with beta-branched side chains ( For example, threonine, valine, isoleucine) and amino acids having aromatic side chains (eg, tyrosine, phenylalanine, tryptophan, histidine).

The terms “polypeptide”, “peptide” and “protein” are used interchangeably herein to refer to polymers of amino acids of any length (if single chain). The polymer can be linear or branched, can include modified amino acids, and can be interrupted by non-amino acids. The term also includes modified amino acid polymers; For example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation or any other manipulation, such as conjugation with a labeling component. Polypeptides can be isolated from natural sources, can be produced by recombinant techniques from eukaryotic or prokaryotic hosts, or can be products of synthetic procedures.

The terms "nucleic acid", "nucleic acid sequence", "nucleotide sequence" or "polynucleotide sequence" and "polynucleotide" are used interchangeably. It refers to a polymer form of nucleotides of any length that are deoxyribonucleotides or ribonucleotides or analogs thereof. The polynucleotide can be single-stranded or double-stranded, and in the case of single-stranded it can be the coding strand or the non-coding (antisense) strand. Polynucleotides can include modified nucleotides, such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides can be intervened by non-nucleotide components. The polynucleotide can be further modified after polymerization, such as by conjugation with a labeling component. The nucleic acid can be a recombinant polynucleotide, or a polynucleotide of genomic, cDNA, semisynthetic or synthetic origin that does not occur in nature or is linked to another polynucleotide in an unnatural arrangement.

As used herein, the term “isolated” refers to a substance that is isolated from its origin or natural environment (eg, natural environment if it is naturally occurring). For example, naturally occurring polynucleotides or polypeptides present in living animals are not isolated, but the same polynucleotides or polypeptides isolated by human intervention from some or all of the substances coexisting in nature are isolated. Such polynucleotides may be part of a vector and / or such polynucleotides or polypeptides may be part of a composition, and such vectors or compositions are still isolated in that they are not part of the environment found in nature.

Various aspects of the invention are described in further detail below. Additional definitions are given throughout the specification.

Dosing regimen

Anti-LAG-3 antibody molecules described herein are used herein to treat (e.g., inhibit, reduce, ameliorate, or prevent) a disorder, such as a hyperproliferative condition or disorder (e.g., cancer), in a subject. It can be administered according to the dosing regimen described. In certain embodiments, the anti-LAG-3 antibody molecule is administered to a subject in a dose of about 200 mg to about 2000 mg, eg, once every 2, 3, or 4 weeks.

In some aspects, the disclosure comprises administering to a subject an anti-LAG-3 antibody molecule (eg, an anti-LAG-3 antibody molecule described herein) at a dose or dosage schedule described herein. It features a method of treating cancer.

In some embodiments, the anti-LAG-3 antibody molecule is administered in a subject at a dose or dosage schedule that binds to, eg saturates, soluble LAG-3. In some embodiments, the anti-LAG-3 antibody molecule is, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, 24, 36, or 48 weeks of administration Within, at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98%, or 99% binding of soluble LAG-3 in a subject, e.g., a dose or dosage that results in saturation It is administered on a schedule.

In some embodiments, the anti-LAG-3 antibody molecule is, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 36, or 48 weeks of administration , In a subject administered at a dose or dose schedule that results in at least 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99% binding, e.g., occupancy of LAG-3 in a tumor do.

In other embodiments, the anti-LAG-3 antibody molecule binds at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98%, or 99% of soluble LAG-3 in a subject, Saturation, for example; Dosage or dose schedule that results in at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98%, or 99% binding, e.g. occupancy, of LAG-3 in a tumor in a subject Is administered as. In embodiments, saturation and / or occupancy occurs, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 36, or 48 weeks of administration.

In some embodiments, the anti-LAG-3 antibody molecule is:

(a) 40% or more of soluble LAG-3 (e.g., 50% or more, 60% or more, 70% or more, 80% or more, 85% or more, 90% or more, 95) in a subject (e.g., blood) % Or more, 99% or more) are bound by anti-LAG-3 antibody molecules; or

(b) 50% or more (e.g., 60% or more, 70% or more, 80% or more, 85% or more, 90% or more, 95% of membrane-bound LAG-3 in a subject (e.g., cancer)) Or more, 99% or more) are bound by anti-LAG-3 antibody molecules

Doses or dose schedules that result in either or both.

In some embodiments, binding of the anti-LAG-3 antibody molecule to soluble LAG-3 is determined in a blood sample (eg, serum sample or plasma sample). In some embodiments, binding of the anti-LAG-3 antibody molecule to membrane-bound LAG-3 is determined in a cancer (eg, cancer sample).

In some embodiments, the subject has anti-LAG-3 binding of the anti-LAG-3 antibody molecule to soluble LAG-3, binding of the anti-LAG-3 antibody molecule to membrane-bound LAG-3, or both. It is determined when the antibody molecule has a steady state minimum level. In some embodiments, the lowest level is the concentration of the anti-LAG-3 antibody molecule about 24 weeks after administration, or the lowest concentration the anti-LAG-3 antibody molecule has reached before the next dose is administered. In some embodiments, binding of the anti-LAG-3 antibody molecule to soluble LAG-3, binding of the anti-LAG-3 antibody molecule to membrane-bound LAG-3, or both are in vitro (e.g., Determined by ELISA or cell-based assays or in vivo (eg, by imaging), measured for example, or predicted from a PK / PD model, eg, the PK / PD model described herein. .

In some embodiments, at least 50% of soluble LAG-3 in a serum sample from a subject is bound by an anti-LAG-3 antibody molecule. In some embodiments, at least 60% of soluble LAG-3 in a serum sample from a subject is bound by an anti-LAG-3 antibody molecule. In some embodiments, at least 70% of soluble LAG-3 in a serum sample from a subject is bound by an anti-LAG-3 antibody molecule. In some embodiments, at least 80% of soluble LAG-3 in a serum sample from a subject is bound by an anti-LAG-3 antibody molecule. In some embodiments, at least 90% of soluble LAG-3 in a serum sample from a subject is bound by an anti-LAG-3 antibody molecule.

In some embodiments, at least 85% of the membrane-bound LAG-3 in a cancer or cancer sample from a subject is bound by an anti-LAG-3 antibody molecule. In some embodiments, at least 90% of the membrane-bound LAG-3 in a cancer or cancer sample from a subject is bound by an anti-LAG-3 antibody molecule. In some embodiments, at least 95% of the membrane-bound LAG-3 in a cancer or cancer sample from a subject is bound by an anti-LAG-3 antibody molecule.

In some embodiments, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of soluble LAG-3 in a serum sample from a subject is bound by an anti-LAG-3 antibody molecule, and the subject At least 85%, at least 90%, or at least 95% of the membrane-bound LAG-3 in a cancer or cancer sample from is bound by an anti-LAG-3 antibody molecule.

In some embodiments, at least 50% of soluble LAG-3 in serum samples from a subject is bound by an anti-LAG-3 antibody molecule, and 90% of membrane-bound LAG-3 in a cancer or cancer sample from a subject Abnormalities are bound by anti-LAG-3 antibody molecules. In some embodiments, at least 60% of soluble LAG-3 in serum samples from a subject is bound by an anti-LAG-3 antibody molecule, and 90% of membrane-bound LAG-3 in a cancer or cancer sample from a subject Abnormalities are bound by anti-LAG-3 antibody molecules. In some embodiments, at least 70% of soluble LAG-3 in serum samples from a subject is bound by an anti-LAG-3 antibody molecule, and 90% of membrane-bound LAG-3 in a cancer or cancer sample from a subject Abnormalities are bound by anti-LAG-3 antibody molecules. In some embodiments, at least 80% of soluble LAG-3 in a serum sample from a subject is bound by an anti-LAG-3 antibody molecule, and 90% of membrane-bound LAG-3 in a cancer or cancer sample from a subject Abnormalities are bound by anti-LAG-3 antibody molecules. In some embodiments, at least 90% of soluble LAG-3 in serum samples from a subject is bound by an anti-LAG-3 antibody molecule, and 90% of membrane-bound LAG-3 in a cancer or cancer sample from a subject Abnormalities are bound by anti-LAG-3 antibody molecules.

In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose or dosage schedule that reduces one or both of the following:

(a) the level of free soluble LAG-3 in a subject, e.g., 40% or less (e.g., 50% or less, 40% or less, 30% or less, 20% or less) of the reference level of free soluble LAG-3 , 15% or less, 10% or less, 5% or less, or 1% or less); or

(b) the level of free membrane-bound LAG-3 in a subject, e.g., 50% or less (e.g., 40% or less, 30% or less, 20%) of the reference level of membrane-bound LAG-3 Or less, 15% or less, 10% or less, 5% or less, or 1% or less).

In some embodiments, the level of free soluble LAG-3 is determined in a blood sample (eg, serum sample or plasma sample). In some embodiments, the reference level of free soluble LAG-3 is the baseline level of free soluble LAG-3 in a subject, eg, according to a dosage schedule, e.g., prior to administration of an anti-LAG-3 antibody molecule.

In some embodiments, the level of free membrane-bound LAG-3 is determined in a cancer (eg, cancer sample). In some embodiments, the reference level of free membrane-bound LAG-3 is free membrane-bound LAG- in a subject, e.g., according to a dosage schedule, e.g., prior to administration of an anti-LAG-3 antibody molecule. This is the baseline level of 3.

In some embodiments, the level of free soluble LAG-3, the level of free membrane-bound LAG-3, or both, is determined when the subject has a steady state knockdown level of the anti-LAG-3 antibody molecule. In some embodiments, the lowest level is the concentration of the anti-LAG-3 antibody molecule about 24 weeks after administration, or the lowest concentration the anti-LAG-3 antibody molecule has reached before the next dose is administered. In some embodiments, the level of free soluble LAG-3, the level of free membrane-bound LAG-3, or both are in vitro (e.g., by ELISA or cell-based assays) or in vivo (e.g. , By imaging), or, for example, measured, or predicted from a PK / PD model, eg, the PK / PD model described herein.

In some embodiments, the level of free soluble LAG-3 is reduced to 50% or less of the reference level of free soluble LAG-3 in serum samples from subjects. In some embodiments, the level of free soluble LAG-3 is reduced to 40% or less of the reference level of free soluble LAG-3 in serum samples from subjects. In some embodiments, the level of free soluble LAG-3 is reduced to 30% or less of the reference level of free soluble LAG-3 in serum samples from subjects. In some embodiments, the level of free soluble LAG-3 is reduced to 20% or less of the reference level of free soluble LAG-3 in serum samples from subjects. In some embodiments, the level of free soluble LAG-3 is reduced to 10% or less of the reference level of free soluble LAG-3 in serum samples from subjects.

In some embodiments, the level of free membrane-bound LAG-3 is reduced to 15% or less of the reference level of free membrane-bound LAG-3 in a cancer or cancer sample from a subject. In some embodiments, the level of free membrane-bound LAG-3 is reduced to 10% or less of the reference level of free membrane-bound LAG-3 in a cancer or cancer sample from a subject. In some embodiments, the level of free membrane-bound LAG-3 is reduced to 5% or less of the reference level of free membrane-bound LAG-3 in a cancer or cancer sample from a subject.

In some embodiments, the level of free soluble LAG-3 is reduced to 50% or less, 40% or less, 30% or less, 20% or less, or 10% or less of the reference level of free soluble LAG-3 in a serum sample from a subject And the level of free membrane-bound LAG-3 is reduced to 15% or less, 10% or less, or 5% or less of the reference level of free membrane-bound LAG-3 in a cancer or cancer sample from a subject.

In some embodiments, the level of free soluble LAG-3 is reduced to 50% or less of the reference level of free soluble LAG-3 in serum samples from the subject, and the level of free membrane-bound LAG-3 is cancer from the subject Or reduced to 10% or less of the reference level of free membrane-bound LAG-3 in cancer samples. In some embodiments, the level of free soluble LAG-3 is reduced to 40% or less of the reference level of free soluble LAG-3 in serum samples from the subject, and the level of free membrane-bound LAG-3 is cancer from the subject Or reduced to 10% or less of the reference level of free membrane-bound LAG-3 in cancer samples. In some embodiments, the level of free soluble LAG-3 is reduced to 30% or less of the reference level of free soluble LAG-3 in serum samples from the subject, and the level of free membrane-bound LAG-3 is cancer from the subject Or reduced to 10% or less of the reference level of free membrane-bound LAG-3 in cancer samples. In some embodiments, the level of free soluble LAG-3 is reduced to 20% or less of the reference level of free soluble LAG-3 in serum samples from the subject, and the level of free membrane-bound LAG-3 is cancer from the subject Or reduced to 10% or less of the reference level of free membrane-bound LAG-3 in cancer samples. In some embodiments, the level of free soluble LAG-3 is reduced to 10% or less of the reference level of free soluble LAG-3 in serum samples from the subject, and the level of free membrane-bound LAG-3 is cancer from the subject Or reduced to 10% or less of the reference level of free membrane-bound LAG-3 in cancer samples.

In certain embodiments, the dose or dosage schedule results in the lowest level (e.g., steady state lowest level) of anti-LAG-3 antibody molecules above the C _crit (e.g., as described in Example 1). equivalence). In some embodiments, C _crit is a concentration below which the non-linear PK is observed. In some embodiments, C _crit is about 60 nM.

In some embodiments, the anti-LAG-3 antibody molecule is administered with a dosing regimen disclosed herein.

In some embodiments, the anti-LAG-3 antibody molecule is about 200 mg to about 1600 mg, about 300 mg to about 1500 mg, about 400 mg to about 1400 mg, about 500 mg to about 1300 mg, about 600 mg to about 1200 mg, about 700 mg to about 1100 mg, about 800 mg to about 1000 mg, about 200 mg to about 1400 mg, about 200 mg to about 1200 mg, about 200 mg to about 1000 mg, about 200 mg to about 800 mg , About 200 mg to about 600 mg, about 200 mg to about 400 mg, about 1400 mg to about 1600 mg, about 1200 mg to about 1600 mg, about 1000 mg to about 1600 mg, about 800 mg to about 1600 mg, about 600 mg to about 1600 mg, about 400 mg to about 1600 mg, about 200 mg to about 600 mg, about 300 mg to about 700 mg, about 400 mg to about 800 mg, about 500 mg to about 900 mg, about 600 mg To about 1000 mg, about 700 mg to about 1100 mg, about 800 mg to about 1200 mg, about 900 mg to about 1300 mg, about 1000 mg to about 1400 mg, about 1100 mg to about 1500 mg, or about 1200 mg to About 1600 mg dose As, for example, is administered once every one, every two or four weeks once a week, every three weeks.

In some embodiments, the anti-LAG-3 antibody molecule is about 200 mg to about 600 mg, about 250 mg to about 550 mg, about 300 mg to about 500 mg, about 350 mg to about 450 mg, about 200 mg to about 400 mg, about 400 mg to about 600 mg, for example, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg Is administered, for example, once every 3 weeks or once every 4 weeks. In certain embodiments, the anti-LAG-3 antibody molecule is from about 300 mg to about 500 mg, e.g., about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about It is administered once every three weeks at a dose of 420 mg, about 440 mg, about 460 mg, about 480 mg, or about 500 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 350 mg to about 450 mg, such as about 400 mg.

In some embodiments, the anti-LAG-3 antibody molecule is about 600 mg to about 1000 mg, about 650 mg to about 950 mg, about 700 mg to about 900 mg, about 750 mg to about 950 mg, about 600 mg to about 800 mg, about 800 mg to about 1000 mg, for example, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg Is administered, for example, once every 3 weeks or once every 4 weeks. In certain embodiments, the anti-LAG-3 antibody molecule is from about 900 mg to about 1100 mg, e.g., about 900 mg, about 920 mg, about 940 mg, about 960 mg, about 980 mg, about 900 mg, about It is administered once every four weeks at a dose of 920 mg, about 940 mg, about 960 mg, about 980 mg, or about 1000 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every four weeks at a dose of about 950 mg to about 1050 mg, such as about 1000 mg.

In some embodiments, the anti-LAG-3 antibody molecule is about 500 mg to about 900 mg, about 550 mg to about 850 mg, about 600 mg to about 800 mg, about 650 mg to about 750 mg, e.g., about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, e.g., once every 3 weeks or every 4 weeks It is administered once. In certain embodiments, the anti-LAG-3 antibody molecule is from about 600 mg to about 800 mg, e.g., about 600 mg, about 620 mg, about 640 mg, about 660 mg, about 680 mg, about 700 mg, about It is administered once every three weeks at a dose of 720 mg, about 740 mg, about 760 mg, about 780 mg, or about 800 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 650 mg to about 750 mg, such as about 700 mg.

In some embodiments, the anti-LAG-3 antibody molecule is about 1200 mg to about 1600 mg, about 1250 mg to about 1550 mg, about 1300 mg to about 1500 mg, about 1350 mg to about 1450 mg, e.g., about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, e.g., once every 3 weeks or 4 weeks It is administered once every time. In certain embodiments, the anti-LAG-3 antibody molecule is from about 1300 mg to about 1500 mg, e.g., about 1300 mg, about 1320 mg, about 1340 mg, about 1360 mg, about 1380 mg, about 1400 mg, about It is administered once every four weeks at a dose of 1420 mg, about 1440 mg, about 1460 mg, about 1480 mg, or about 1500 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every 4 weeks at a dose of about 1350 mg to about 1450 mg, such as about 1400 mg.

In some embodiments, the anti-LAG-3 antibody molecule is about 400 mg to about 700 mg, about 450 mg to about 650 mg, about 500 mg to about 600 mg, about 450 mg to about 550 mg, about 500 mg to about 600 mg, about 550 mg to about 650 mg, about 600 mg to about 700 mg, about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, for example about 400 mg , About 450 mg, about 500 mg, about 533 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, for example, once every 4 weeks. In certain embodiments, the anti-LAG-3 antibody molecule is from about 450 mg to about 650 mg, e.g., about 450 mg, about 500 mg, about 533 mg, about 550 mg, about 600 mg, or about 650 mg The dose is administered once every 4 weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every 4 weeks at a dose of about 500 mg to about 650 mg, such as about 533 mg or about 600 mg.

In some embodiments, the anti-LAG-3 antibody molecule is about 2000 mg or less, about 1900 mg or less, about 1800 mg or less, about 1700 mg or less, about 1600 mg or less, about 1500 mg or less, about 1400 mg or less, about 1300 mg or less, about 1200 mg or less, about 1100 mg or less, about 1000 mg or less, about 900 mg or less, about 800 mg or less, about 700 mg or less, about 600 mg or less, about 533 mg or less, about 500 mg or less, about 400 It is administered once every two weeks, once every three weeks, or once every four weeks at a dose of less than or equal to about 300 mg, less than or equal to about 250 mg, or less than or equal to about 200 mg.

In some embodiments, the disorder is cancer, eg, a cancer described herein. In certain embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a brain tumor, eg, a glioblastoma, neuroeducation, or recurrent brain tumor. In some embodiments, the cancer is pancreatic cancer, eg, advanced pancreatic cancer. In some embodiments, the cancer is skin cancer, such as melanoma (eg, stage II-IV melanoma, HLA-A2 positive melanoma, unresectable melanoma, or metastatic melanoma), or Merkel cell carcinoma. . In some embodiments, the cancer is renal cancer, eg, renal cell carcinoma (RCC) (eg, metastatic renal cell carcinoma). In some embodiments, the cancer is breast cancer, eg, metastatic breast carcinoma or stage IV breast carcinoma, such as triple negative breast cancer (TNBC). In some embodiments, the cancer is a virus-associated cancer. In some embodiments, the cancer is anal canal cancer (eg, squamous cell carcinoma of the anal canal). In some embodiments, the cancer is cervical cancer (eg, squamous cell carcinoma of the cervix). In some embodiments, the cancer is gastric cancer (eg, Epstein Barr virus (EBV) positive gastric cancer or gastric or gastro-esophageal junction carcinoma). In some embodiments, the cancer is head and neck cancer (eg, HPV positive and negative squamous cell head and neck cancer (SCCHN)). In some embodiments, the cancer is nasopharyngeal cancer (NPC). In some embodiments, the cancer is penile cancer (eg, squamous cell carcinoma of the penis). In some embodiments, the cancer is vaginal or vulvar cancer (eg, squamous cell carcinoma of the vagina or vulva). In some embodiments, the cancer is colorectal cancer, e.g., recurrent colorectal cancer or metastatic colorectal cancer, e.g., microsatellite unstable colorectal cancer, microsatellite stable colorectal cancer, mismatch recovery proficient colorectal cancer, or mismatch repair Deficient colorectal cancer. In some embodiments, the cancer is lung cancer, eg, non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is blood cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is a lymphoma, such as Hodgkin's lymphoma (HL) or diffuse versus B cell lymphoma (DLBCL) (eg, recurrent or refractory HL or DLBCL). In some embodiments, the cancer is myeloma.

In other embodiments, the cancer is a high-MSI cancer. In some embodiments, the cancer is metastatic cancer. In other embodiments, the cancer is advanced cancer. In other embodiments, the cancer is recurrent or refractory cancer. In other embodiments, the cancer is an unresectable cancer.

In one embodiment, the cancer is Merkel cell carcinoma. In other embodiments, the cancer is melanoma. In other embodiments, the cancer is breast cancer, eg, triple negative breast cancer (TNBC) or HER2-negative breast cancer. In other embodiments, the cancer is renal cell carcinoma (eg, clear cell renal cell carcinoma (CCRCC) or non-transparent cell renal cell carcinoma (nccRCC)). In other embodiments, the cancer is thyroid cancer, eg, anaplastic thyroid carcinoma (ATC). In other embodiments, the cancer is a neuroendocrine tumor (NET), eg, atypical lung carcinoid tumor or pancreas, gastrointestinal (GI) tract, or NET in the lung. In certain embodiments, the cancer is non-small cell lung cancer (NSCLC) (eg, squamous NSCLC or non-squamous NSCLC). In certain embodiments, the cancer is fallopian tube cancer. In certain embodiments, the cancer is high-microsatellite unstable colorectal cancer (high-MSI CRC) or microsatellite stable colorectal cancer (MSS CRC).

In some embodiments, the anti-LAG-3 antibody molecule is administered in combination with an anti-PD-1 antibody molecule (eg, the anti-PD-1 antibody molecule described herein). Without wishing to be bound by theory, in some embodiments, the anti-LAG-3 therapy, as observed in mice (Woo et al. Cancer Research 72: 917-927 (2012)), anti-PD-1 therapy It is expected to have an additive effect in combination with. The anti-PD-1 antibody molecule can be a chemotherapeutic agent (e.g., platinum agent (e.g. carboplatin, cisplatin, oxaliplatin, or tetraplatin)) or a nucleotide analog or precursor analog (e.g., capecitabine) )). Without wishing to be bound by theory, in some embodiments, the addition of chemotherapeutic agents, alone or in combination with anti-PD-1 immunotherapy, makes the tumor more immune-responsive and / or optimal anti-tumor. It is believed to further enhance the efficacy of anti-LAG-3 immunotherapy by altering the tumor microenvironment to achieve an immune response.

In certain embodiments, the anti-PD-1 antibody molecule is administered at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every 4 weeks or about 200 mg to about 400 mg (e.g., About 300 mg) once every three weeks. In some embodiments, the anti-PD-1 antibody molecule is administered once every 4 weeks at a dose of about 300 mg to about 500 mg (eg, about 400 mg). In some embodiments, the anti-PD-1 antibody molecule is administered once every three weeks at a dose of about 200 mg to about 400 mg (eg, about 300 mg).

In certain embodiments, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to 500 mg (e.g., about 400 mg), and the anti-PD-1 antibody molecule is about 200 mg To about 400 mg (eg, about 300 mg) once every three weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to 500 mg (e.g., about 400 mg), and the anti-PD-1 antibody molecule is about 300 mg To about 500 mg (eg, about 400 mg) once every 4 weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every 4 weeks at a dose of about 700 mg to 900 mg (e.g., about 800 mg), and the anti-PD-1 antibody molecule is about 200 mg To about 400 mg (eg, about 300 mg) once every three weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every 4 weeks at a dose of about 700 mg to 900 mg (e.g., about 800 mg), and the anti-PD-1 antibody molecule is about 300 mg To about 500 mg (eg, about 400 mg) once every 4 weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every 4 weeks at a dose of about 500 mg to 650 mg (e.g., about 533 mg or about 600 mg), and the anti-PD-1 antibody molecule Is administered once every three weeks at a dose of about 200 mg to about 400 mg (eg, about 300 mg). In certain embodiments, the anti-LAG-3 antibody molecule is administered once every 4 weeks at a dose of about 500 mg to 650 mg (e.g., about 533 mg or about 600 mg), and the anti-PD-1 antibody molecule Is administered once every four weeks at a dose of about 300 mg to about 500 mg (eg, about 400 mg).

In some embodiments, the anti-TIM-3 antibody molecule is a chemotherapeutic agent (e.g., a platinum agent (e.g. carboplatin, cisplatin, oxaliplatin, or tetraplatin)) or a nucleotide analog or precursor analog (e.g. For example, capecitabine)). In some embodiments, the chemotherapeutic agent is a platinum agent. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin. In certain embodiments, the platinum agent is oxaliplatin. In certain embodiments, the platinum agent is tetraplatin.

In some embodiments, the chemotherapeutic agent is a nucleotide analog or precursor analog. In certain embodiments, the nucleotide analog or precursor analog is capecitabine.

In certain embodiments, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to 500 mg (e.g., about 400 mg), and a chemotherapeutic agent (e.g., a platinum agent, For example, carboplatin) is administered once every three weeks at a dose to achieve an area under the curve (AUC) of about 4 to about 8 or about 5 to about 7 (e.g., AUC of about 6). .

In certain embodiments, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to 500 mg (e.g., about 400 mg), and the anti-PD-1 antibody molecule is about 200 mg To about 400 mg (e.g., about 300 mg) once every 3 weeks, and chemotherapeutic agents (e.g., platinum agents, e.g. carboplatin) are from about 4 to about 8 or It is administered once every three weeks at a dose to achieve an area under the curve (AUC) of about 5 to about 7 (eg, AUC of about 6).

In certain embodiments, the anti-LAG-3 antibody molecule is LAG525 and the anti-PD-1 antibody molecule is PDR001 (spartalizumab).

In some embodiments, the anti-LAG-3 antibody molecule is LAG525, and the chemotherapeutic agent is a platinum agent. In certain embodiments, the anti-LAG-3 antibody molecule is LAG525, and the platinum agent is carboplatin. In certain embodiments, the anti-LAG-3 antibody molecule is LAG525, and the platinum agent is cisplatin. In certain embodiments, the anti-LAG-3 antibody molecule is LAG525 and the platinum agent is oxaliplatin. In certain embodiments, the anti-LAG-3 antibody molecule is LAG525, and the platinum agent is tetraplatin.

In some embodiments, the anti-LAG-3 antibody molecule is LAG525, the chemotherapeutic agent is a platinum agent, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab). In certain embodiments, the anti-LAG-3 antibody molecule is LAG525, the platinum agent is carboplatin, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab). In certain embodiments, the anti-LAG-3 antibody molecule is LAG525, the platinum agent is cisplatin, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab). In certain embodiments, the anti-LAG-3 antibody molecule is LAG525, the platinum agent is oxaliplatin, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab). In certain embodiments, the anti-LAG-3 antibody molecule is LAG525, the platinum agent is tetraplatin, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab).

In some embodiments, the anti-LAG-3 antibody molecule is LAG525, and the chemotherapeutic agent is a nucleotide analog or precursor analog. In certain embodiments, the anti-LAG-3 antibody molecule is LAG525, and the nucleotide analog or precursor analog is capecitabine.

In some embodiments, the anti-LAG-3 antibody molecule is LAG525, the chemotherapeutic agent is a nucleotide analog or precursor analog, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab). In certain embodiments, the anti-LAG-3 antibody molecule is LAG525, the nucleotide analog or precursor analog is capecitabine, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab).

Any dose disclosed herein can be repeated once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, or more.

Antibody molecule

Disclosed herein are methods, compositions, and formulations comprising antibody molecules that bind to mammals, such as humans, LAG-3. For example, the antibody molecule specifically binds an epitope on LAG-3, eg, a linear or conformational epitope (eg, an epitope as described herein).

The term “antibody molecule” as used herein refers to a protein comprising at least one immunoglobulin variable domain sequence, eg an immunoglobulin chain or fragment thereof. The term “antibody molecule” includes, for example, monoclonal antibodies (including full-length antibodies with immunoglobulin Fc regions). In one embodiment, the antibody molecule comprises a full-length antibody or full-length immunoglobulin chain. In one embodiment, the antibody molecule comprises an antigen-binding or functional fragment of a full-length antibody or full-length immunoglobulin chain. In one embodiment, the antibody molecule is a multispecific antibody molecule, e.g., it comprises a plurality of immunoglobulin variable domain sequences, wherein the first of the plurality of immunoglobulin variable domain sequences is binding specific for a first epitope. And the second immunoglobulin variable domain sequence of the plurality has binding specificity to the second epitope. In one embodiment, the multispecific antibody molecule is a bispecific antibody molecule.

In one embodiment, the antibody molecule is a monospecific antibody molecule and binds a single epitope. For example, a monospecific antibody molecule can have multiple immunoglobulin variable domain sequences that each bind to the same epitope.

In one embodiment, the antibody molecule is a multispecific antibody molecule, e.g., it comprises a plurality of immunoglobulin variable domain sequences, wherein the first of the plurality of immunoglobulin variable domain sequences has binding specificity for a first epitope. And the second immunoglobulin variable domain sequence of the plurality has binding specificity for the second epitope. In one embodiment, the first and second epitopes are on the same antigen, for example on the same protein (or subunit of a multicellular protein). In one embodiment, the first and second epitopes overlap. In one embodiment, the first and second epitopes do not overlap. In one embodiment, the first and second epitopes are on different antigens, for example different proteins (or different subunits of multimeric proteins). In one embodiment, the multispecific antibody molecule comprises a third, fourth or fifth immunoglobulin variable domain. In one embodiment, the multispecific antibody molecule is a bispecific antibody molecule, trispecific antibody molecule or quadspecific antibody molecule.

In one embodiment, the multispecific antibody molecule is a bispecific antibody molecule. Bispecific antibodies have specificity for up to 2 antigens. Bispecific antibody molecules are characterized by a first immunoglobulin variable domain sequence having binding specificity for a first epitope and a second immunoglobulin variable domain sequence having binding specificity for a second epitope. In one embodiment, the first and second epitopes are on the same antigen, for example on the same protein (or subunit of a multicellular protein). In one embodiment, the first and second epitopes overlap. In one embodiment, the first and second epitopes do not overlap. In one embodiment, the first and second epitopes are on different antigens, for example different proteins (or different subunits of multimeric proteins). In one embodiment, the bispecific antibody molecule comprises a heavy chain variable domain sequence having a binding specificity for a first epitope and a light chain variable domain sequence and a heavy chain variable domain sequence having a binding specificity for a second epitope and a light chain variable domain sequence. do. In one embodiment, a bispecific antibody molecule comprises a half antibody with binding specificity for a first epitope and a half antibody with binding specificity for a second epitope. In one embodiment, the bispecific antibody molecule comprises a half antibody having a binding specificity for a first epitope or a fragment thereof, and a half antibody having a binding specificity for a second epitope or a fragment thereof. In one embodiment, the bispecific antibody molecule comprises a scFv having a binding specificity for a first epitope or a fragment thereof, and a scFv having a binding specificity for a second epitope or a fragment thereof. In one embodiment, the first epitope is located on LAG-3 and the second epitope is PD-1, TIM-3, CEACAM (eg, CEACAM-1 and / or CEACAM-5), PD-L1, or Located on PD-L2.

Protocols for generating multi-specific (eg, bispecific or trispecific) or heterodimeric antibody molecules are known in the art; For example, the “knob in hole” approach described, for example, in US5731168; Electrostatic steering Fc pairing as described, for example, in WO 09/089004, WO 06/106905 and WO 2010/129304; Strand exchange engineered domain (SEED) heterodimer formation as described, for example, in WO 07/110205; Fab arm exchange as described, for example, in WO 08/119353, WO 2011/131746, and WO 2013/060867; Dual antibody conjugates, such as described in US4433059, for example, by antibody crosslinking to produce bispecific structures using heterobifunctional reagents having amine-reactive groups and sulfhydryl reactive groups; Bispecific antibody determinants produced by recombining half antibodies (heavy chain-light chain pairs or Fabs) from different antibodies through a reduction and oxidation cycle of disulfide bonds between two heavy chains, eg, as described in US 4444878; Trifunctional antibodies, such as the three Fab 'fragments crosslinked, for example, via sulfhydryl reactive groups, as described in US5273743; A biosynthetic binding protein, eg, a pair of scFvs, as described in US5534254, crosslinked via, for example, a C-terminal tail, preferably via disulfide or amine-reactive chemical crosslinking; Bifunctional antibodies, e.g., Fab fragments having different binding specificities dimerized via leucine zippers (e.g., c-fos and c-jun) that replaced the constant domains, as described in US5582996; Bispecific and oligospecific monovalent- and oligovalent receptors, e.g., as described in US5591828, for example, between a CH1 region of one antibody and the VH region of another antibody typically associated with a light chain The VH-CH1 region of two antibodies (2 Fab fragments) linked through; Bispecific DNA-antibody conjugates, for example crosslinking of antibodies or Fab fragments, such as through double-stranded fragments of DNA, as described in US5635602; Bispecific fusion proteins, eg, expression constructs, as described in US5637481, for example, with two scFvs, with a hydrophilic helix peptide linker between them and the entire constant region; Multivalent and multispecific binding proteins, e.g., as described in US5837242, a first domain having a binding region of an Ig heavy chain variable region, generally referred to as a diabody, and a binding region of an Ig light chain variable region Dimers of polypeptides having a second domain with (higher-dimensional structures that also produce bispecific, trispecific or tetraspecific molecules are also disclosed); Minibody constructs, wherein the linked VL and VH chains, as described, for example, in US5837821, are further linked by peptide spacers to antibody hinge regions and CH3 regions that can be dimerized to form bispecific / multivalent molecules; Use a short peptide linker (eg, 5 or 10 amino acids), which can form dimers, trimers and tetramers to form bispecific diabodies, eg, as described in US5844094, or Or VH and VL domains linked in either orientation with no linkers at all; A VH domain (or VL in a family member) linked by a peptide linkage by a C-terminal crosslinkable group further associated with the VL domain to form a series of FVs (or scFvs), eg, as described in US5864019 Domain); And non-covalent or chemical crosslinking, for example, to form homodivalent, heterodivalent, trivalent, and tetravalent structures, using both scFV or diabody type formats, as described, for example, in US5869620. Single chain binding polypeptides having both VH and VL domains linked via a peptide linker, combined in a multivalent structure through. Additional exemplary multispecific and bispecific molecules and methods of making them are, for example, US5910573, US5932448, US5959083, US5989830, US6005079, US6239259, US6294353, US6333396, US6476198, US6511663, US6670453, US6743896, US6809185, US6833441, US7129330, US7183076, US7521056, US7527787, US7534866, US7612181, US2002 / 004587A1, US2002 / 076406A1, US2002 / 103345A1, US2003 / 207346A1, US2003 / 211078A1, US2004 / 219643A1, US2004 / 220388A1, US2004 / 242847403A1, US2005 / 242847403 004352A1, US2005 / 069552A1, US2005 / 079170A1, US2005 / 100543A1, US2005 / 136049A1, US2005 / 136051A1, US2005 / 163782A1, US2005 / 266425A1, US2006 / 083747A1, US2006 / 120960A1, US2006 / 204493A1, US2006 / 263367A909, US2007 / 2633670041 US2007 / 087381A1, US2007 / 128150A1, US2007 / 141049A1, US2007 / 154901A1, US2007 / 274985A1, US2008 / 050370A1, US2008 / 069820A1, US2008 / 152645A1, US2008 / 171855A1, US2008 / 241884A1, US2008 / 254512A1, US2008 / 260738A1 130106A1, US2009 / 148905A1, US2009 / 155275A1, US2009 / 162359A1, US2009 / 162360A1, US 2009 / 175851A1, US2009 / 175867A1, US2009 / 232811A1, US2009 / 234105A1, US2009 / 263392A1, US2009 / 274649A1, EP346087A2, WO00 / 06605A2, WO02 / 072635A2, WO04 / 081051A1, WO06 / 020258A2, WO2007 / 044887A2, WO2007 / 09587338 It is found in WO2007 / 137760A2, WO2008 / 119353A1, WO2009 / 021754A2, WO2009 / 068630A1, WO91 / 03493A1, WO93 / 23537A1, WO94 / 09131A1, WO94 / 12625A2, WO95 / 09917A1, WO96 / 37621A2, WO99 / 64460A1. The contents of the above-referenced application are incorporated herein by reference in their entirety.

In other embodiments, the anti-LAG-3 antibody molecule (e.g., monospecific, bispecific, or multispecific antibody molecule) is another partner, e.g., as a fusion molecule, e.g., a fusion protein. , Covalently linked to, eg fused to, eg a protein, eg 1, 2 or more cytokines. In other embodiments, the fusion molecule comprises one or more proteins, such as one, two or more cytokines. In one embodiment, the cytokine is an interleukin (IL) selected from 1, 2, 3 or more of IL-1, IL-2, IL-12, IL-15 or IL-21. In one embodiment, the bispecific antibody molecule has a first binding specificity to a first target (eg, LAG-3), a second to a second target (eg, PD-1 or TIM-3). It has binding specificity and is optionally linked to an interleukin (eg, IL-12) domain, eg, full-length IL-12 or a portion thereof.

“Fusion protein” and “fusion polypeptide” refer to polypeptides having at least two parts covalently linked together, each part being a polypeptide having different properties. The properties can be biological properties, such as in vitro or in vivo activity. Properties can also be simple chemical or physical properties, such as binding to a target molecule, catalysis of a reaction, and the like. The two moieties can be linked directly by a single peptide bond or via a peptide linker, but are within reading frames of each other.

In one embodiment, antibody molecules include diabodies, and single-chain molecules, as well as antigen-binding fragments of antibodies (eg, Fab, F (ab ') ₂ , and Fv). For example, the antibody molecule may include a heavy chain (H) variable domain sequence (abbreviated herein as VH) and a light chain (L) variable domain sequence (abbreviated herein as VL). In one embodiment, the antibody molecule comprises or consists of heavy and light chains (referred to herein as a half antibody). In another example, the antibody molecule comprises two heavy chain (H) variable domain sequences and two light chain (L) variable domain sequences to form two antigen binding sites, such as Fab, Fab ', F (ab') ₂ , Fc, Fd, Fd ', Fv, single chain antibody (e.g. scFv), single variable domain antibody, Diabody (Dab) (bivalent and bispecific), and chimeric (e.g. humanized) antibodies Can be produced by modification of the whole antibody or can be newly synthesized using recombinant DNA technology. These functional antibody fragments retain the ability to selectively bind their respective antigens or receptors. Antibodies and antibody fragments include any class of antibodies, including, but not limited to, IgG, IgA, IgM, IgD, and IgE, and any subclass of antibodies (e.g., IgG1, IgG2, IgG3, and IgG4) It may be from The preparation of the antibody molecule can be monoclonal or polyclonal. The antibody molecule can also be a human, humanized, CDR-grafted or in vitro generated antibody. The antibody may have a heavy chain constant region selected from, for example, IgG1, IgG2, IgG3 or IgG4. The antibody may also have a light chain selected from, for example, kappa or lambda. The term “immunoglobulin” (Ig) is used interchangeably herein with the term “antibody”.

Examples of antigen-binding fragments of antibody molecules include: (i) Fab fragments, monovalent fragments consisting of the VL, VH, CL and CH1 domains; (ii) a F (ab ') 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a diabody (dAb) fragment consisting of a VH domain; (vi) camels or camelized variable domains; (vii) Single chain Fv (scFv) (e.g., Bird et al. (1988) Science 242: 423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85: 5879 -5883); (viii) Single domain antibodies. These antibody fragments are obtained using conventional techniques known to those skilled in the art, and the fragments are screened for utility in the same way as intact antibodies.

The term “antibody” includes intact molecules as well as functional fragments thereof. The constant region of an antibody is altered to modify the properties of the antibody (e.g., to increase or decrease one or more of Fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function or complement function), e.g. For example, it can be mutated.

The antibody molecule can also be a single domain antibody. Single domain antibodies can include antibodies whose complementarity determining regions are part of a single domain polypeptide. Examples include, but are not limited to, heavy chain antibodies, naturally lacking light chain antibodies, single domain antibodies derived from conventional 4-chain antibodies, engineered antibodies and single domain scaffolds other than those derived from antibodies. . Single domain antibodies can be any of the art, or any future single domain antibody. Single domain antibodies can be derived from any species including mouse, human, camel, llama, fish, shark, goat, rabbit and cow. According to another aspect of the invention, a single domain antibody is a naturally occurring single domain antibody known as a heavy chain antibody lacking a light chain. Such single domain antibodies are disclosed, for example, in WO 94/04678. For reasons of clarity, this variable domain derived from a heavy chain antibody that naturally lacks a light chain is known herein as a VHH or nanobody to distinguish it from the conventional VH of a four chain immunoglobulin. Such VHH molecules can be derived from antibodies produced in camel species, such as camels, llamas, dromedaries, alpacas, and guanaco. Species other than the camelid family can naturally produce heavy chain antibodies that lack the light chain; Such VHHs are within the scope of the present invention.

The VH and VL regions can be subdivided into hypervariable regions called “complementarity determining regions” (CDRs), with more conserved regions called “framework regions” (FR or FW) interposed therebetween.

The scope of the framework regions and CDRs is precisely defined by a number of methods (Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242; Chothia, C. et al. (1987) J. Mol. Biol. 196: 901-917; and AbM definitions used by Oxford Molecular's AbM antibody modeling software). In general, see, eg, Protein Sequence and Structure Analysis of Antibody Variable Domains. In: Antibody Engineering Lab Manual (Ed .: Duebel, S. and Kontermann, R., Springer-Verlag, Heidelberg).

As used herein, the terms “complementarity determining region”, and “CDR” refer to the sequence of amino acids within an antibody variable region that confers antigen specificity and binding affinity. Generally, there are three CDRs (HCDR1, HCDR2, and HCDR3) within each heavy chain variable region and three CDRs (LCDR1, LCDR2, and LCDR3) within each light chain variable region.

The exact amino acid sequence boundaries of a given CDR are described in Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme), Al-Lazikani et al., (1997) JMB 273,927-948 ("Cotia" numbering scheme)] Can be determined using any of the well-known schemes. CDRs defined according to the “Chothia” numbering scheme as used herein are also sometimes referred to as “hypervariable loops”.

For example, under Kabat, CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3); CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3). CDR amino acids in VH under Chothia are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); The amino acid residues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3). By combining the CDR definitions of both Kabat and Chothia, the CDRs are amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in human VH and amino acid residues 24- in human VL. 34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3).

In general, unless specifically indicated, an anti-LAG-3 antibody molecule may include any combination of one or more Kabat CDRs and / or Chothia hypervariable loops. In one embodiment, the following definitions are used for the anti-LAG-3 antibody molecule: HCDR1 according to the combined CDR definition of both Kabat and Chothia and HCCDR 2-3 and LCCDR 1 according to the CDR definition of Kabat. -3. Under all definitions, each VH and VL typically comprises three CDRs and four FRs arranged in the following sequence from amino-terminal to carboxy-terminal: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

“Immunoglobulin variable domain sequence” as used herein refers to an amino acid sequence capable of forming the structure of an immunoglobulin variable domain. For example, the sequence can include all or part of the amino acid sequence of a naturally occurring variable domain. For example, the sequence may or may not include one, two or more N- or C-terminal amino acids, or other modifications compatible with the formation of a protein structure.

The term “antigen-binding site” refers to a portion of an antibody molecule comprising a determinant that forms an interface that binds to an LAG-3 polypeptide or epitope thereof. With respect to proteins (or protein mimetics), the antigen-binding site typically comprises one or more loops (at least of four amino acids or amino acid mimetics) that form an interface that binds the LAG-3 polypeptide. Typically, the antigen-binding site of an antibody molecule comprises at least 1 or 2 CDRs and / or hypervariable loops, or more typically at least 3, 4, 5 or 6 CDRs and / or hypervariable loops.

The terms "competition" or "cross-competition" prevent the binding of an anti-LAG-3 antibody molecule, e.g., an anti-LAG-3 antibody molecule provided herein, to a target, e.g., human LAG-3. It is used interchangeably herein to refer to the ability of an antibody molecule. Interference with binding can be direct or indirect (eg, through allosteric adjustment of the antibody molecule or target). The extent to which an antibody molecule can interfere with the binding of another antibody molecule to a target, and thus whether it can be said to compete, use a competitive binding assay, such as FACS assay, ELISA or Biacore assay. Can be determined. In some embodiments, the competition binding assay is a quantitative competition assay. In some embodiments, the first anti-LAG-3 antibody molecule has a binding to the target of the first antibody molecule of at least 10%, such as at least 20%, in a competitive binding assay (e.g., a competition assay described herein). , 30% or more, 40% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98 It is said to compete with the second anti-LAG-3 antibody molecule for binding to the target when reduced by at least 99%, at least 99%.

As used herein, the term “monoclonal antibody” or “monoclonal antibody composition” refers to the preparation of antibody molecules of single molecular composition. Monoclonal antibody compositions exhibit a single binding specificity and affinity for a particular epitope. Monoclonal antibodies can be produced by hybridoma technology or by methods that do not use hybridoma technology (eg, recombinant methods).

An “effective human” protein is a protein that does not elicit a neutralizing antibody response, such as a human anti-murine antibody (HAMA) response. HAMA can be problematic in many situations, for example, when the antibody molecule is administered repeatedly, eg, in the treatment of a chronic or recurrent disease state. The HAMA response is due to increased antibody clearance from serum (see, eg, Saleh et al., Cancer Immunol. Immunother. 32: 180-190 (1990)) and also due to potential allergic reactions (eg, (See LoBuglio et al., Hybridoma, 5: 5117-5123 (1986)). Repeated antibody administration may potentially render it invalid.

The antibody molecule can be a polyclonal or monoclonal antibody. In other embodiments, antibodies can be produced recombinantly, for example, by phage display or a combination method.

Phage display and combination methods for generating antibodies are known in the art (see, eg, Ladner et al. US Patent No. 5,223,409; Kang et al. International Publication No. WO 92/18619; Dower et al. International Publication No. WO 91/17271; Winter et al. International Publication WO 92/20791; Markland et al.International Publication No. WO 92/15679; Breitling et al.International Publication WO 93/01288; McCafferty et al.International Publication No. WO 92 / 01047; Garrard et al. International Publication No. WO 92/09690; Ladner et al. International Publication No. WO 90/02809; Fuchs et al. (1991) Bio / Technology 9: 1370-1372; Hay et al. (1992) Hum Antibody Hybridomas 3: 81-85; Huse et al. (1989) Science 246: 1275-1281; Griffths et al. (1993) EMBO J 12: 725-734; Hawkins et al. (1992) J Mol Biol 226: 889 -896; Clackson et al. (1991) Nature 352: 624-628; Gram et al. (1992) PNAS 89: 3576-3580; Garrad et al. (1991) Bio / Technology 9: 1373-1377; Hoogenboom et al (1991) Nuc Acid Res 19: 4133-4137; and Barbas et al. (1991) PNAS 88: 7978-7982] (the contents of all of which are incorporated herein by reference).

In one embodiment, the antibody is a fully human antibody (eg, an antibody prepared in a mouse genetically engineered to produce an antibody from a human immunoglobulin sequence), or a non-human antibody, such as a rodent (mouse or rat). , Goats, primates (eg monkeys), camel antibodies. Preferably, the non-human antibody is a rodent (mouse or rat antibody). Methods for producing rodent antibodies are known in the art.

Human monoclonal antibodies can be generated using transgenic mice carrying the human immunoglobulin gene rather than the mouse system. Splenocytes from these transgenic mice immunized with the antigen of interest are used to produce hybridomas that secrete human mAbs with specific affinity for epitopes from human proteins (eg, Wood et al. International Application WO 91/00906, Kucherlapati et al. PCT Publication WO 91/10741; Lonberg et al. International Application WO 92/03918; Kay et al. International Application 92/03917; Lonberg, N. et al. 1994 Nature 368 : 856-859; Green, LL et al. 1994 Nature Genet. 7: 13-21; Morrison, SL et al. 1994 Proc. Natl. Acad. Sci. USA 81: 6851-6855; Bruggeman et al. 1993 Year Immunol 7: 33-40; Tuaillon et al. 1993 PNAS 90: 3720-3724; Bruggeman et al. 1991 Eur J Immunol 21: 1323-1326).

The antibody may be a variable region or a portion thereof, such as a CDR, produced in a non-human organism, such as a rat or mouse. Chimeric, CDR-grafted and humanized antibodies are within the present invention. Antibodies within the present invention are produced, for example, in a variable framework or constant region, which have been modified in a non-human organism, such as a rat or mouse, to reduce antigenicity in a human, for example.

Chimeric antibodies can be produced by recombinant DNA techniques known in the art (Robinson et al., International Patent Publication PCT / US86 / 02269; Akira, et al., European Patent Application 184,187; Taniguchi, M. , European Patent Application 171,496; Morrison et al., European Patent Application 173,494; Neuberger et al., International Application WO 86/01533; Cabilly et al.US Patent No. 4,816,567; Cabilly et al., European Patent Application 125,023; Better et al (1988 Science 240: 1041-1043); Liu et al. (1987) PNAS 84: 3439-3443; Liu et al., 1987, J. Immunol. 139: 3521-3526; Sun et al. (1987) PNAS 84: 214-218; Nishimura et al., 1987, Canc. Res. 47: 999-1005; Wood et al. (1985) Nature 314: 446-449; and Shaw et al., 1988, J. Natl Cancer Inst 80: 1553-1559).

The humanized or CDR-grafted antibody will have at least 1 or 2 (of heavy and / or light chain immunoglobulin chains), but generally all 3 acceptor CDRs, replaced by donor CDRs. The antibody can be replaced by at least a portion of a non-human CDR, or only a portion of the CDRs can be replaced by a non-human CDR. It is only necessary for the humanized antibody to replace the number of CDRs required to bind PD-1. Preferably, the donor will be a rodent antibody, such as a rat or mouse antibody, and the recipient will be a human framework or human consensus framework. Typically, an immunoglobulin that provides a CDR is called a “donor”, and an immunoglobulin that provides a framework is called a “receptor”. In one embodiment, the donor immunoglobulin is non-human (eg, rodent). Receptor frameworks are naturally occurring (eg, human) frameworks or consensus frameworks, or sequences that are at least about 85%, preferably 90%, 95%, 99% or more identical thereto.

The term “consensus sequence” as used herein refers to a sequence formed from the most frequently occurring amino acids (or nucleotides) in a family of related sequences (see, eg, Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, DE1987) )] Reference). In the protein family, each position in the consensus sequence is occupied by the amino acids that occur most frequently at that position in the family. If two amino acids occur equally frequently, either can be included in the consensus sequence. "Consensus framework" refers to the framework region in the consensus immunoglobulin sequence.

Antibodies can be humanized by methods known in the art (eg, [Morrison, SL, 1985, Science 229: 1202-1207], [Oi et al., 1986, BioTechniques 4: 214], and See Queen et al. US 5,585,089, US 5,693,761 and US 5,693,762 (the contents of all of which are incorporated herein by reference).

Humanized or CDR-grafted antibodies can be produced by CDR-grafting or CDR substitution, where one, two or all CDRs of the immunoglobulin chain can be replaced. See, eg, US Patents 5,225,539; Jones et al. 1986 Nature 321: 552-525; Verhoeyan et al. 1988 Science 239: 1534; Beidler et al. 1988 J. Immunol. 141: 4053-4060; Winter US 5,225,539 (the contents of all of which are expressly incorporated herein by reference). Winter describes a CDR-grafting method that can be used to prepare the humanized antibodies of the invention (UK patent application GB 2188638A, filed March 26, 1987; Winter US 5,225,539, the contents of which are hereby expressly incorporated by reference) )).

In addition, humanized antibodies to which specific amino acids have been substituted, deleted or added are within the scope of the present invention. Criteria for selecting amino acids from donors are described in US 5,585,089, such as column 12-16 of US 5,585,089, such as column 12-16 of US 5,585,089, the contents of which are incorporated herein by reference. Other techniques for humanizing antibodies are described in Padlan et al. EP 519596 A1, published on December 23, 1992.

The antibody molecule can be a single chain antibody. Single-chain antibodies (scFV) can be engineered (e.g., Colcher, D. et al. (1999) Ann NY Acad Sci 880: 263-80; and Reiter, Y. (1996) Clin Cancer Res 2: 245-52). Single chain antibodies can be dimerized or multiplexed to produce multivalent antibodies with specificity for different epitopes of the same target protein.

In another embodiment, the antibody molecule is selected from the heavy chain constant regions of, e.g., IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD and IgE, in particular for example of IgG1, IgG2, IgG3 and IgG4 For example, human) heavy chain constant region selected from heavy chain constant region. In another embodiment, the antibody molecule has a light chain constant region selected from (eg, human) light chain constant regions of kappa or lambda. The constant region is altered to modify the properties of the antibody (e.g., to increase or decrease one or more of Fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function and / or complement function), e.g. For example, it can be mutated. In one embodiment the antibody has an effector function; The complement can be fixed. In other embodiments the antibody does not mobilize effector cells; The complement is not fixed. In another embodiment, the antibody has reduced or no ability to bind an Fc receptor. For example, an antibody is an isotype or subtype, fragment or other mutant that does not support binding to an Fc receptor and has, for example, a mutated or deleted Fc receptor binding region.

Methods for altering antibody constant regions are known in the art. Antibodies with altered function, e.g. effector ligands, such as FcRs on a cell or C1 component of complement, can be produced by replacing at least one amino acid residue in the constant portion of the antibody with a different residue (e.g. For example, see EP 388,151 A1, US Patent No. 5,624,821 and US Patent No. 5,648,260 (the contents of all of which are incorporated herein by reference). Similar types of alterations that reduce or eliminate these functions when applied to murine or other species immunoglobulins can be described.

The antibody molecule can be derivatized or linked to another functional molecule (eg, another peptide or protein). As used herein, “derivatized” antibody molecules are modified. Methods of derivatization include, but are not limited to, the addition of fluorescent moieties, radionucleotides, toxins, enzymes or affinity ligands such as biotin. Accordingly, antibody molecules of the invention are intended to include derivatized and otherwise modified forms of the antibodies described herein, including immunoadhesive molecules. For example, an antibody molecule can be one or more other molecular entities, such as another antibody (e.g., a bispecific antibody or diabody), a detectable agent, a cytotoxic agent, a pharmaceutical agent, and / or another molecule ( For example, it can be functionally linked (by chemical coupling, gene fusion, non-covalent association or others) to a protein or peptide capable of mediating the association of an antibody or antibody portion with a streptavidin core region or polyhistidine tag).

One type of derivatized antibody molecule is produced by crosslinking two or more antibodies (of the same type, or, for example, different types to produce a bispecific antibody). Suitable crosslinking agents are heterobifunctional (eg, m-maleimidobenzoyl-N-hydroxysuccinimide esters) having two distinct reactive groups separated by suitable spacers, or homobifunctional (eg For example, disuccinimidyl suberate). Such linkers are available from Pierce Chemical Company of Rockford, Illinois.

Useful detectable agents capable of derivatizing the antibody molecule of the invention are fluorescent compounds, various enzymes, prosthetic groups, luminescent substances, bioluminescent substances, fluorescence emitting metal atoms, such as europium (Eu) and other lanthanides, and It can be derivatized (or labeled) to include radioactive materials (described below). Exemplary fluorescent detectable agents include fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-1-naphthalenesulfonyl chloride, picoerythrin, and the like. Antibodies can also be derivatized with detectable enzymes such as alkaline phosphatase, horseradish peroxidase, β-galactosidase, acetylcholinesterase, glucose oxidase, and the like. When an antibody is derivatized with a detectable enzyme, it is detected by adding additional reagents that the enzyme uses to produce a detectable reaction product. For example, when horseradish peroxidase, a detectable agent, is present, the addition of hydrogen peroxide and diaminobenzidine leads to a detectable colored reaction product. Antibody molecules can also be derivatized with a prosthetic group (eg, streptavidin / biotin and avidin / biotin). For example, antibodies can be derivatized with biotin and can be detected through indirect measurement of avidin or streptavidin binding. Examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or picoerythrin; Examples of luminescent materials include luminol; Examples of bioluminescent materials include luciferase, luciferin and equerin.

The labeled antibody molecule comprises (i) isolating a predetermined antigen by standard techniques, such as affinity chromatography or immunoprecipitation; (ii) detecting a predetermined antigen (eg, in cell lysate or cell supernatant) to assess the abundance and pattern of expression of the protein; (iii) can be used, for example, diagnostically and / or experimentally in a number of situations, including monitoring protein levels in tissue as part of a clinical trial procedure, for example, to determine the efficacy of a given treatment regimen. .

The antibody molecule can be conjugated to another molecular entity, typically a labeling or therapeutic (eg, cytotoxic or cytostatic) agent or moiety. Radioactive isotopes can be used for diagnostic or therapeutic uses.

The present invention provides radiolabeled antibody molecules and methods of labeling the same. In one embodiment, a method of labeling an antibody molecule is disclosed. The method involves contacting the antibody molecule with a chelating agent to produce a conjugated antibody.

As discussed above, antibody molecules can be conjugated to therapeutic agents. The therapeutically active radioisotope has already been mentioned. Examples of other therapeutic agents are Taxol, Cytocalcin B, Gramicidine D, Ethidium bromide, Emethine, Mitomycin, Etoposide, Tenofoside, Vincristine, Vinblastine, Colchicine, Doxorubicin, Daunorubicin, Dihydroxy anthracin dione, mitoxantrone, mitramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoid, procaine, tetracaine, lidocaine, propranolol, puromycin, maytansinoid, e.g. maytansinoid Tancinol (see, eg, US Pat. No. 5,208,020), CC-1065 (see, eg, US Pat. No. 5,475,092, 5,585,499, 5,846, 545) and analogs or homologs thereof. Therapeutic agents include anti-metabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g. mechlorethamine, thioepaclo Rambucil, CC-1065, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C and cis-dichlorodiamine platinum ( II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin)), bleomycin, Mitramycin and anthramycin (AMC)), and antimitotic agents (eg, vincristine, vinblastine, taxol and maytansinoid).

In one aspect, the disclosure provides a method of providing a target binding molecule that specifically binds a target disclosed herein, such as a LAG-3 receptor. For example, the target binding molecule is an antibody molecule. The method includes: homologous to the corresponding portion of the human target protein (with at least 70, 75, 80, 85, 87, 90, 92, 94, 95, 96, 97, 98% identical), but at least Provide a target protein comprising at least a portion of a non-human protein, wherein one amino acid (eg, at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 amino acids) is different; Obtaining antibody molecules that specifically bind to the antigen; Assessing the efficacy of a binding agent in modulating the activity of a target protein. The method may further include administering a binding agent (eg, antibody molecule) or derivative (eg, humanized antibody molecule) to the human subject.

The present disclosure provides isolated nucleic acid molecules encoding the antibody molecules, vectors and host cells thereof. Nucleic acid molecules include, but are not limited to, RNA, genomic DNA and cDNA.

Exemplary anti-LAG-3 antibody molecules

In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule as disclosed under US 2015/0259420 published on September 17, 2015 under the heading "Antibody Molecules for LAG-3 and Uses thereof", This is incorporated by reference in its entirety.

In one embodiment, the anti-LAG-3 antibody molecule is from a heavy chain and a light chain variable region comprising the amino acid sequence set forth in Table 5 (e.g., the heavy chain of BAP050-clone I or BAP050-clone J disclosed in Table 5 and At least 1, 2, 3, 4, 5 or 6 complementarity determining regions (CDRs) (or collectively all CDRs) from the light chain variable region sequence) or from those encoded by the nucleotide sequences set forth in Table 5 Includes. In some embodiments, CDRs are according to the Kabat definition (eg, as shown in Table 5). In some embodiments, the CDR is according to the Chothia definition (eg, as shown in Table 5). In some embodiments, the CDRs follow the combined CDR definitions of both Kabat and Chothia (eg, as shown in Table 5). In one embodiment, the combination of the Kabat and Chothia CDRs of VH CDR1 comprises the amino acid sequence GFTLTNYGMN (SEQ ID NO: 766). In one embodiment, one or more (or collectively all CDRs) of the CDRs are 1, 2, 3, 4, 5, 6 compared to those encoded by the amino acid sequence set forth in Table 5, or the nucleotide sequence set forth in Table 5 Dog or more changes, eg, amino acid substitutions (eg, conservative amino acid substitutions) or deletions.

In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain variable region comprising the VHCDR1 amino acid sequence of SEQ ID NO: 701, the VHCDR2 amino acid sequence of SEQ ID NO: 702, and the VHCDR3 amino acid sequence of SEQ ID NO: 703 ( VH); And a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 710, the VLCDR2 amino acid sequence of SEQ ID NO: 711, and the VLCDR3 amino acid sequence of SEQ ID NO: 712, each of which is disclosed in Table 5 It is done.

In one embodiment, the anti-LAG-3 antibody molecule is VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 736 or 737, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 738 or 739, and SEQ ID NO: A VH comprising VHCDR3 encoded by the nucleotide sequence of 740 or 741; And VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 746 or 747, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 748 or 749, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 750 or 751. Including VL, each of which is disclosed in Table 5. In one embodiment, the anti-LAG-3 antibody molecule is VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 758 or 737, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 759 or 739, and SEQ ID NO: A VH comprising VHCDR3 encoded by the nucleotide sequence of 760 or 741; And VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 746 or 747, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 748 or 749, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 750 or 751. Including VL, each of which is disclosed in Table 5.

In one embodiment, the anti-LAG-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 706, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 706. Including VH. In one embodiment, the anti-LAG-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 718, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 718. Including VL. In one embodiment, the anti-LAG-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 724, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 724. Including VH. In one embodiment, the anti-LAG-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 730, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 730. Including VL. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 706 and a VL comprising the amino acid sequence of SEQ ID NO: 718. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 724 and a VL comprising the amino acid sequence of SEQ ID NO: 730.

In one embodiment, the antibody molecule is by a nucleotide sequence of SEQ ID NO: 707 or 708, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 707 or 708 Coded VH. In one embodiment, the antibody molecule is by a nucleotide sequence of SEQ ID NO: 719 or 720, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 719 or 720 Includes coded VL. In one embodiment, the antibody molecule is by a nucleotide sequence of SEQ ID NO: 725 or 726, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 725 or 726 Coded VH. In one embodiment, the antibody molecule is by a nucleotide sequence of SEQ ID NO: 731 or 732, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 731 or 732. Includes coded VL. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 707 or 708 and a VL encoded by the nucleotide sequence of SEQ ID NO: 719 or 720. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 725 or 726 and a VL encoded by the nucleotide sequence of SEQ ID NO: 731 or 732.

In one embodiment, the anti-LAG-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 709, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 709. Includes heavy chains. In one embodiment, the anti-LAG-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 721, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 721. Includes light chains. In one embodiment, the anti-LAG-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 727, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 727. Includes heavy chains. In one embodiment, the anti-LAG-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 733, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 733. Includes light chains. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 709 and a light chain comprising the amino acid sequence of SEQ ID NO: 721. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 727 and a light chain comprising the amino acid sequence of SEQ ID NO: 733.

In one embodiment, the antibody molecule is by a nucleotide sequence of SEQ ID NO: 716 or 717, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 716 or 717 Coded heavy chain. In one embodiment, the antibody molecule is by a nucleotide sequence of SEQ ID NO: 722 or 723, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 722 or 723 Coded light chain. In one embodiment, the antibody molecule is by a nucleotide sequence of SEQ ID NO: 728 or 729, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 728 or 729. Coded heavy chain. In one embodiment, the antibody molecule is by a nucleotide sequence of SEQ ID NO: 734 or 735, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 734 or 735 Coded light chain. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 716 or 717 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 722 or 723. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 728 or 729 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 734 or 735.

Antibody molecules described herein can be made by the vectors, host cells, and methods described in US 2015/0259420, which is incorporated by reference in its entirety.

Table 5. Amino acid and nucleotide sequences of exemplary anti-LAG-3 antibody molecules

In one embodiment, the anti-LAG-3 antibody molecule is BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050 -hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050 (Ser) (example For , BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050- hum19-Ser, or BAP050-hum20-Ser), the amino acid sequence of any of BAP050-clone-F, BAP050-clone-G, BAP050-clone-H, BAP050-clone-I, or BAP050-clone-J; Or as described in Table 1 of US 2015/0259420; Or is encoded by the nucleotide sequence in Table 1; Or at least a sequence that is substantially identical to any of the above sequences (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical). One or two heavy chain variable domains (optionally including constant regions), at least one or two light chain variable domains (optionally including constant regions), or both.

In another embodiment, the anti-LAG-3 antibody molecule is an antibody described herein, such as BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07 , BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050 -hum20, huBAP050 (Ser) (e.g. , BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050- hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15- Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, or BAP050-hum20-Ser), BAP050-clone-F, BAP050-clone-G, BAP050-clone-H, BAP050-clone-I, or BAP050-clone An antibody selected from any of -J; Or as described in Table 1 of US 2015/0259420; Or is encoded by the nucleotide sequence in Table 1; Or a heavy chain variable of a sequence that is substantially identical to any of the above sequences (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) At least 1, 2, or 3 complementarity determining regions (CDRs) from a region and / or a light chain variable region.

In another embodiment, the anti-LAG-3 antibody molecule is at least 1, 2, or from a heavy chain variable region comprising the amino acid sequence set forth in Table 1 of US 2015/0259420, or the one encoded by the nucleotide sequence set forth in Table 1 Includes 3 CDRs (or collectively all CDRs). In one embodiment, one or more (or collectively all CDRs) of the CDRs are 1, 2, 3, 4, 5, 6 compared to those encoded by the amino acid sequences set forth in Table 1, or the nucleotide sequences set forth in Table 1 Dogs or more changes, eg amino acid substitutions or deletions.

In another embodiment, the anti-LAG-3 antibody molecule is at least 1, 2, or from a light chain variable region comprising the amino acid sequence set forth in Table 1 of US 2015/0259420, or the one encoded by the nucleotide sequence set forth in Table 1 Includes 3 CDRs (or collectively all CDRs). In one embodiment, one or more (or collectively all CDRs) of the CDRs are 1, 2, 3, 4, 5, 6 compared to those encoded by the amino acid sequences set forth in Table 1, or the nucleotide sequences set forth in Table 1 Dogs or more changes, eg amino acid substitutions or deletions. In certain embodiments, the anti-PD-L1 antibody molecule comprises substitutions in the light chain CDRs, eg, one or more substitutions in the CDR1, CDR2 and / or CDR3 of the light chain.

In another embodiment, the anti-LAG-3 antibody molecule comprises at least 1 from the heavy chain and light chain variable regions comprising the amino acid sequence set forth in Table 1, or the nucleotide sequence set forth in Table 1 of US 2015/0259420, 2, 3, 4, 5 or 6 CDRs (or collectively all CDRs). In one embodiment, one or more (or collectively all CDRs) of the CDRs are 1, 2, 3, 4, 5, 6 compared to those encoded by the amino acid sequences set forth in Table 1, or the nucleotide sequences set forth in Table 1 Dogs or more changes, eg amino acid substitutions or deletions.

Other exemplary anti-LAG-3 antibody molecules

In one embodiment, the anti-LAG-3 antibody molecule is BMS-986016 (Bristol-Myers Squibb), also known as BMS986016. BMS-986016 and other anti-LAG-3 antibodies are disclosed in WO 2015/116539 and US 9,505,839, the entire contents of which are incorporated by reference. In one embodiment, the anti-LAG-3 antibody molecule comprises, for example, one or more (or collectively all CDR sequences) of the CDR sequences of BMS-986016, as disclosed in Table 6, heavy or light chain variable region sequences. , Or heavy or light chain sequences.

In one embodiment, the anti-LAG-3 antibody molecule is TSR-033 (Tesaro). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more (or collectively all CDR sequences) of the CDR sequences of TSR-033, heavy or light chain variable region sequences, or heavy or light chain sequences.

In one embodiment, the anti-LAG-3 antibody molecule is IMP731 or GSK2831781 (GSK and Prima Biomed). IMP731 and other anti-LAG-3 antibodies are disclosed in WO 2008/132601 and US 9,244,059, the entire contents of which are incorporated by reference. In one embodiment, the anti-LAG-3 antibody molecule is, for example, one or more (or collectively all CDR sequences) of the CDR sequences of IMP731 as disclosed in Table 6, heavy or light chain variable region sequences, or Heavy chain or light chain sequence. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more (or collectively all CDR sequences) of the CDR sequences of GSK2831781, heavy or light chain variable region sequences, or heavy or light chain sequences.

In one embodiment, the anti-LAG-3 antibody molecule is IMP761 (Prima Biomed). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more (or collectively all CDR sequences) of the CDR sequences of IMP761, heavy or light chain variable region sequences, or heavy or light chain sequences.

Further known anti-LAG-3 antibodies are, for example, WO 2008/132601, WO 2010/019570, WO 2014/140180, WO 2015/116539, WO 2015/200119, WO 2016/028672, US 9,244,059, US 9,505,839, the entire contents of which are incorporated by reference.

In one embodiment, an anti-LAG-3 antibody is an antibody that competes for and / or binds to binding of one of the anti-LAG-3 antibodies described herein with the same epitope on LAG-3.

In one embodiment, the anti-LAG-3 inhibitor is a soluble LAG-3 protein, for example IMP321 (Prima Biomed), as disclosed in WO 2009/044273, incorporated herein by reference in its entirety.

Table 6. Amino acid sequences of other exemplary anti-LAG-3 antibody molecules

PD-1 inhibitor

In certain embodiments, the anti-LAG-3 antibody molecules described herein are administered in combination with a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is PDR001 or Spartalizumab (Novartis), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck & Company) & Co)), Pidilizumab (CureTech), MEDI0680 (Medimmune), REGN2810 (Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer) ), BGB-A317 (Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune).

Exemplary PD-1 inhibitors

In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule. In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule as described under the heading "Antibody molecules against PD-1 and uses thereof" in US 2015/0210769, published July 30, 2015, This is incorporated by reference in its entirety.

In one embodiment, the anti-PD-1 antibody molecule is from a heavy and light chain variable region comprising the amino acid sequence set forth in Table 1 (e.g., BAP049-clone-E or BAP049-clone-B disclosed in Table 1). At least 1, 2, 3, 4, 5 or 6 complementarity determining regions (CDRs) (or collectively all CDRs) from the heavy and light chain variable region sequences), or from those encoded by the nucleotide sequences set forth in Table 1 ). In some embodiments, the CDRs are according to the Kabat definition (eg, as shown in Table 1). In some embodiments, the CDRs are according to the Chothia definition (eg, as shown in Table 1). In some embodiments, CDRs are subject to the combined CDR definitions of both Kabat and Chothia (eg, as shown in Table 1). In one embodiment, the combination of the Kabat and Chothia CDRs of VH CDR1 comprises the amino acid sequence GYTFTTYWMH (SEQ ID NO: 541). In one embodiment, one or more (or collectively all CDRs) of the CDRs are 1, 2, 3, 4, 5, 6 compared to those encoded by the amino acid sequences set forth in Table 1, or the nucleotide sequences set forth in Table 1 Dog or more changes, eg, amino acid substitutions (eg, conservative amino acid substitutions) or deletions.

In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain variable region comprising the VHCDR1 amino acid sequence of SEQ ID NO: 501, the VHCDR2 amino acid sequence of SEQ ID NO: 502, and the VHCDR3 amino acid sequence of SEQ ID NO: 503 ( VH); And a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 510, the VLCDR2 amino acid sequence of SEQ ID NO: 511, and the VLCDR3 amino acid sequence of SEQ ID NO: 512, each of which is disclosed in Table 1 It is done.

In one embodiment, the antibody molecule is VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 524, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 525, and VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 526 VH containing; And a VL comprising VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 529, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 530, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 531. , Each is disclosed in Table 1.

In one embodiment, the anti-PD-1 antibody molecule comprises an amino acid sequence of SEQ ID NO: 506, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 506. Including VH. In one embodiment, the anti-PD-1 antibody molecule comprises an amino acid sequence of SEQ ID NO: 520, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 520. Including VL. In one embodiment, the anti-PD-1 antibody molecule comprises an amino acid sequence of SEQ ID NO: 516, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 516. Including VL. In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506 and a VL comprising the amino acid sequence of SEQ ID NO: 520. In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506 and a VL comprising the amino acid sequence of SEQ ID NO: 516.

In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 507, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 507. Includes. In one embodiment, the antibody molecule is by a nucleotide sequence of SEQ ID NO: 521 or 517, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 521 or 517 Includes coded VL. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 507 and a VL encoded by the nucleotide sequence of SEQ ID NO: 521 or 517.

In one embodiment, the anti-PD-1 antibody molecule comprises an amino acid sequence of SEQ ID NO: 508, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 508. Includes heavy chains. In one embodiment, the anti-PD-1 antibody molecule comprises an amino acid sequence of SEQ ID NO: 522, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 522. Includes light chains. In one embodiment, the anti-PD-1 antibody molecule comprises an amino acid sequence of SEQ ID NO: 518, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 518. Includes light chains. In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508 and a light chain comprising the amino acid sequence of SEQ ID NO: 522. In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508 and a light chain comprising the amino acid sequence of SEQ ID NO: 518.

In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 509. Includes. In one embodiment, the antibody molecule is by a nucleotide sequence of SEQ ID NO: 523 or 519, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 523 or 519 Coded light chain. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519.

Antibody molecules described herein can be made by the vectors, host cells, and methods described in US 2015/0210769, which is incorporated by reference in its entirety.

Table 1. Amino acid and nucleotide sequences of exemplary anti-PD-1 antibody molecules

Other exemplary PD-1 inhibitors

In one embodiment, the anti-PD-1 antibody molecule is nivolumab (Bristol-Myers Squibb), which is also MDX-1106, MDX-1106-04, ONO-4538, BMS-936558, or OPDIVO® Also known as. Nivolumab (clone 5C4) and other anti-PD-1 antibodies are disclosed in US 8,008,449 and WO 2006/121168, which is incorporated by reference in its entirety. In one embodiment, the anti-PD-1 antibody molecule comprises, for example, one or more (or collectively all CDR sequences) of the Nivolumab CDR sequences as disclosed in Table 2, heavy or light chain variable region sequences, Or heavy or light chain sequences.

In one embodiment, the anti-PD-1 antibody molecule is pembrolizumab (Merck & Company), also known as lambrolizumab, MK-3475, MK03475, SCH-900475, or KEYTRUDA® have. Pembrolizumab and other anti-PD-1 antibodies are described in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44], US 8,354,509, and WO 2009/114335, incorporated herein by reference in its entirety. In one embodiment, the anti-PD-1 antibody molecule comprises one or more (or collectively all CDR sequences), heavy or light chain variable region sequences of the CDR sequences of pembrolizumab, e.g., as disclosed in Table 2. , Or heavy or light chain sequences.

In one embodiment, the anti-PD-1 antibody molecule is pidilizumab (Curetech), also known as CT-011. Pidilizumab and other anti-PD-1 antibodies are described in Rosenblatt, J. et al. (2011) J Immunotherapy 34 (5): 409-18], US 7,695,715, US 7,332,582, and US 8,686,119, the entire contents of which are incorporated by reference. In one embodiment, the anti-PD-1 antibody molecule comprises, for example, one or more (or collectively all CDR sequences) of a pyridizumab CDR sequence, as disclosed in Table 2, heavy or light chain variable region sequences. , Or heavy or light chain sequences.

In one embodiment, the anti-PD-1 antibody molecule is MEDI0680 (Medynum), also known as AMP-514. MEDI0680 and other anti-PD-1 antibodies are disclosed in US 9,205,148 and WO 2012/145493, the entire contents of which are incorporated by reference. In one embodiment, the anti-PD-1 antibody molecule comprises one or more (or collectively all CDR sequences) of the CDR sequences of MEDI0680, heavy or light chain variable region sequences, or heavy or light chain sequences.

In one embodiment, the anti-PD-1 antibody molecule is REGN2810 (Regeneron). In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences of REGN2810 (or collectively all CDR sequences), heavy or light chain variable region sequences, or heavy or light chain sequences.

In one embodiment, the anti-PD-1 antibody molecule is PF-06801591 (Pfizer). In one embodiment, the anti-PD-1 antibody molecule comprises one or more (or collectively all CDR sequences) of the CDR sequences of PF-06801591, heavy or light chain variable region sequences, or heavy or light chain sequences.

In one embodiment, the anti-PD-1 antibody molecule is BGB-A317 or BGB-108 (Bagin). In one embodiment, the anti-PD-1 antibody molecule comprises one or more (or collectively all CDR sequences) of the CDR sequences of BGB-A317 or BGB-108, a heavy or light chain variable region sequence, or a heavy or light chain sequence. Includes.

In one embodiment, the anti-PD-1 antibody molecule is INCSHR1210 (Insight), which is also known as INCSHR01210 or SHR-1210. In one embodiment, the anti-PD-1 antibody molecule comprises one or more (or collectively all CDR sequences) of the CDR sequences of INCSHR1210, heavy or light chain variable region sequences, or heavy or light chain sequences.

In one embodiment, the anti-PD-1 antibody molecule is TSR-042 (Tesaro), also known as ANB011. In one embodiment, the anti-PD-1 antibody molecule comprises one or more (or collectively all CDR sequences) of the CDR sequences of TSR-042, heavy or light chain variable region sequences, or heavy or light chain sequences.

Additional known anti-PD-1 antibodies are, for example, WO 2015/112800, WO 2016/092419, WO 2015/085847, WO 2014/179664, WO 2014/194302, WO 2014/209804, WO 2015/200119 , US 8,735,553, US 7,488,802, US 8,927,697, US 8,993,731, and US 9,102,727, the entire contents of which are incorporated by reference.

In one embodiment, the anti-PD-1 antibody is an antibody that competes for and / or binds to one of the anti-PD-1 antibodies described herein with the same epitope on PD-1.

In one embodiment, the PD-1 inhibitor is a peptide that inhibits the PD-1 signaling pathway, eg, as described in US 8,907,053, which is incorporated by reference in its entirety. In one embodiment, the PD-1 inhibitor is an extracellular or PD- of PD-L1 or PD-L2 fused to an immunoadhesin (eg, a constant region (eg, an Fc region of an immunoglobulin sequence)). 1 is an immunoadhesin containing a binding moiety. In one embodiment, the PD-1 inhibitor is AMP-224 (eg, B7-DCIg (Amplyem) disclosed in WO 2010/027827 and WO 2011/066342, incorporated herein by reference in its entirety).

Table 2. Amino acid sequences of other exemplary anti-PD-1 antibody molecules

PD-L1 inhibitor

In certain embodiments, the anti-LAG-3 antibody molecules described herein are administered in combination with a PD-L1 inhibitor. In some embodiments, the PD-L1 inhibitor is FAZ053 (nopartis), atezolizumab (Genentech / Roche), abelumab (Merck Serono and Pfizer), durvalumab (MedEye / AstraZeneca), or BMS-936559 (Bristol-Myers Squibb).

Exemplary PD-L1 inhibitors

In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule. In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule as disclosed under the heading “Antibody molecule against PD-L1 and uses thereof” in US 2016/0108123, published April 21, 2016, This is incorporated by reference in its entirety.

In one embodiment, the anti-PD-L1 antibody molecule is from a heavy and light chain variable region comprising the amino acid sequences set forth in Table 3 (e.g., a heavy chain of BAP058-clone O or BAP058-clone N disclosed in Table 3) and At least 1, 2, 3, 4, 5 or 6 complementarity determining regions (CDRs) (or collectively all CDRs) from the light chain variable region sequence) or from those encoded by the nucleotide sequences set forth in Table 3 Includes. In some embodiments, CDRs are according to the Kabat definition (eg, as shown in Table 3). In some embodiments, CDRs are according to the Chothia definition (eg, as shown in Table 3). In some embodiments, CDRs are subject to the combined CDR definitions of both Kabat and Chothia (eg, as shown in Table 3). In one embodiment, the combination of the Kabat and Chothia CDRs of VH CDR1 comprises the amino acid sequence GYTFTSYWMY (SEQ ID NO: 647). In one embodiment, one or more (or collectively all CDRs) of the CDRs are 1, 2, 3, 4, 5, 6 compared to those encoded by the amino acid sequence set forth in Table 3, or the nucleotide sequence set forth in Table 3 Dog or more changes, eg, amino acid substitutions (eg, conservative amino acid substitutions) or deletions.

In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain variable region comprising the VHCDR1 amino acid sequence of SEQ ID NO: 601, the VHCDR2 amino acid sequence of SEQ ID NO: 602, and the VHCDR3 amino acid sequence of SEQ ID NO: 603 ( VH); And a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 609, the VLCDR2 amino acid sequence of SEQ ID NO: 610, and the VLCDR3 amino acid sequence of SEQ ID NO: 611, each in Table 3 It is done.

In one embodiment, the anti-PD-L1 antibody molecule is VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 628, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 629, and the nucleotide sequence of SEQ ID NO: 630 VH comprising VHCDR3 encoded by; And a VL comprising VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 633, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 634, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 635, and , Each is disclosed in Table 3.

In one embodiment, the anti-PD-L1 antibody molecule comprises an amino acid sequence of SEQ ID NO: 606, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 606. Including VH. In one embodiment, the anti-PD-L1 antibody molecule comprises the amino acid sequence of SEQ ID NO: 616, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 616. Including VL. In one embodiment, the anti-PD-L1 antibody molecule comprises the amino acid sequence of SEQ ID NO: 620, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 620. Including VH. In one embodiment, the anti-PD-L1 antibody molecule comprises an amino acid sequence of SEQ ID NO: 624, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 624. Including VL. In one embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 606 and a VL comprising the amino acid sequence of SEQ ID NO: 616. In one embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 620 and a VL comprising the amino acid sequence of SEQ ID NO: 624.

In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 607, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 607. Includes. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 617, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 617. Includes. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 621, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 621. Includes. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 625, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 625. Includes. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 607 and a VL encoded by the nucleotide sequence of SEQ ID NO: 617. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 621 and a VL encoded by the nucleotide sequence of SEQ ID NO: 625.

In one embodiment, the anti-PD-L1 antibody molecule comprises an amino acid sequence of SEQ ID NO: 608, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 608. Includes heavy chains. In one embodiment, the anti-PD-L1 antibody molecule comprises the amino acid sequence of SEQ ID NO: 618, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 618. Includes light chains. In one embodiment, the anti-PD-L1 antibody molecule has the amino acid sequence of SEQ ID NO: 622, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 622. Includes heavy chains. In one embodiment, the anti-PD-L1 antibody molecule comprises an amino acid sequence of SEQ ID NO: 626, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 626. Includes light chains. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 608 and a light chain comprising the amino acid sequence of SEQ ID NO: 618. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 622 and a light chain comprising the amino acid sequence of SEQ ID NO: 626.

In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 615, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 615. Includes. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 619, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 619. Includes. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 623, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 623. Includes. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 627, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 627. Includes. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 615 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 619. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 623 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 627.

Antibody molecules described herein can be made by the vectors, host cells, and methods described in US 2016/0108123, which is incorporated by reference in its entirety.

Table 3. Amino acid and nucleotide sequences of exemplary anti-PD-L1 antibody molecules

Other exemplary PD-L1 inhibitors

In one embodiment, the anti-PD-L1 antibody molecule is atezolizumab (Genentech / Roche), which is also known as MPDL3280A, RG7446, RO5541267, YW243.55.S70, or TECENTRIQ ™. . Atezolizumab and other anti-PD-L1 antibodies are disclosed in US 8,217,149, which is incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises, for example, one or more (or collectively all CDR sequences) of athezolizumab CDR sequences as disclosed in Table 4, heavy or light chain variable region sequences. , Or heavy or light chain sequences.

In one embodiment, the anti-PD-L1 antibody molecule is Avelumab (Merck Serono and Pfizer), also known as MSB0010718C. Avelumab and other anti-PD-L1 antibodies are disclosed in WO 2013/079174, which is incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises, for example, one or more (or collectively all CDR sequences) of Avelumab's CDR sequences as set forth in Table 4, heavy or light chain variable region sequences, Or heavy or light chain sequences.

In one embodiment, the anti-PD-L1 antibody molecule is durvalumab (Medmunem / AstraZeneca), also known as MEDI4736. Durvalumab and other anti-PD-L1 antibodies are disclosed in US 8,779,108, which is incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises, for example, one or more (or collectively all CDR sequences) of durvalumab's CDR sequences as disclosed in Table 4, heavy or light chain variable region sequences. , Or heavy or light chain sequences.

In one embodiment, the anti-PD-L1 antibody molecule is BMS-936559 (Bristol-Myers Squibb), also known as MDX-1105 or 12A4. BMS-936559 and other anti-PD-L1 antibodies are disclosed in US 7,943,743 and WO 2015/081158, which is incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule is one or more (or collectively all CDR sequences) of the CDR sequences of BMS-936559, e.g., as disclosed in Table 4, heavy or light chain variable region sequences. , Or heavy or light chain sequences.

Additional known anti-PD-L1 antibodies are, for example, WO 2015/181342, WO 2014/100079, WO 2016/000619, WO 2014/022758, WO 2014/055897, WO 2015/061668, WO 2013/079174 , WO 2012/145493, WO 2015/112805, WO 2015/109124, WO 2015/195163, US 8,168,179, US 8,552,154, US 8,460,927, and US 9,175,082, the entire contents of which are incorporated by reference.

In one embodiment, the anti-PD-L1 antibody is an antibody that competes for and / or binds to one of the anti-PD-L1 antibodies described herein with the same epitope on PD-L1.

Table 4. Amino acid sequences of other exemplary anti-PD-L1 antibody molecules

TIM-3 inhibitors

In certain embodiments, the anti-LAG-3 antibody molecules described herein are administered in combination with a TIM-3 inhibitor. In some embodiments, the TIM-3 inhibitor is MGB453 (Nopartis) or TSR-022 (Tesaro).

Exemplary TIM-3 inhibitors

In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule. In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule as disclosed under US 2015/0218274 published on August 6, 2015 under the heading "Antibody molecules against TIM-3 and uses thereof", This is incorporated by reference in its entirety.

In one embodiment, the anti-TIM-3 antibody molecule comprises heavy and light chain variables from the heavy and light chain variable regions comprising the amino acid sequences set forth in Table 7 (e.g., ABTIM3-hum11 or ABTIM3-hum03 disclosed in Table 7). From the region sequence), or at least 1, 2, 3, 4, 5 or 6 complementarity determining regions (CDRs) (or collectively all CDRs) from those encoded by the nucleotide sequences set forth in Table 7. . In some embodiments, CDRs are according to the Kabat definition (eg, as shown in Table 7). In some embodiments, CDRs conform to the Chothia definition (eg, as shown in Table 7). In one embodiment, one or more (or collectively all CDRs) of the CDRs are 1, 2, 3, 4, 5, 6 compared to those encoded by the amino acid sequences set forth in Table 7, or the nucleotide sequences set forth in Table 7. Dog or more changes, eg, amino acid substitutions (eg, conservative amino acid substitutions) or deletions.

In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain variable region comprising the VHCDR1 amino acid sequence of SEQ ID NO: 801, the VHCDR2 amino acid sequence of SEQ ID NO: 802, and the VHCDR3 amino acid sequence of SEQ ID NO: 803 ( VH); And a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 810, the VLCDR2 amino acid sequence of SEQ ID NO: 811, and the VLCDR3 amino acid sequence of SEQ ID NO: 812, each of which is disclosed in Table 7 It is done. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain variable region comprising the VHCDR1 amino acid sequence of SEQ ID NO: 801, the VHCDR2 amino acid sequence of SEQ ID NO: 820, and the VHCDR3 amino acid sequence of SEQ ID NO: 803 ( VH); And a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 810, the VLCDR2 amino acid sequence of SEQ ID NO: 811, and the VLCDR3 amino acid sequence of SEQ ID NO: 812, each of which is disclosed in Table 7 It is done.

In one embodiment, the anti-TIM-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 806, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 806. Including VH. In one embodiment, the anti-TIM-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 816, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 816. Including VL. In one embodiment, the anti-TIM-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 822, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 822. Including VH. In one embodiment, the anti-TIM-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 826, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 826. Including VL. In one embodiment, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 806 and a VL comprising the amino acid sequence of SEQ ID NO: 816. In one embodiment, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 822 and a VL comprising the amino acid sequence of SEQ ID NO: 826.

In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 807, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 807. Includes. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 817, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 817. Includes. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 823, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 823. Includes. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 827, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 827. Includes. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 807 and a VL encoded by the nucleotide sequence of SEQ ID NO: 817. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 823 and a VL encoded by the nucleotide sequence of SEQ ID NO: 827.

In one embodiment, the anti-TIM-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 808, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 808. Includes heavy chains. In one embodiment, the anti-TIM-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 818, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 818. Includes light chains. In one embodiment, the anti-TIM-3 antibody molecule comprises an amino acid sequence of SEQ ID NO: 824, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 824. Includes heavy chains. In one embodiment, the anti-TIM-3 antibody molecule comprises the amino acid sequence of SEQ ID NO: 828, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 828. Includes light chains. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 808 and a light chain comprising the amino acid sequence of SEQ ID NO: 818. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 824 and a light chain comprising the amino acid sequence of SEQ ID NO: 828.

In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 809, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 809. Includes. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 819, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 819. Includes. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 825, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 825. Includes. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 829, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 829. Includes. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 809 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 819. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 825 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 829.

Antibody molecules described herein can be made by the vectors, host cells, and methods described in US 2015/0218274, which is incorporated by reference in its entirety.

Table 7. Amino acid and nucleotide sequences of exemplary anti-TIM-3 antibody molecules

Other exemplary TIM-3 inhibitors

In one embodiment, the anti-TIM-3 antibody molecule is TSR-022 (AnaptysBio / Thesaro). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more (or collectively all CDR sequences) of the CDR sequences of TSR-022, heavy or light chain variable region sequences, or heavy or light chain sequences. In one embodiment, the anti-TIM-3 antibody molecule comprises, for example, one or more (or collectively all CDR sequences) of the APE5137 or APE5121 CDR sequences as disclosed in Table 8, heavy or light chain variable region sequences. , Or heavy or light chain sequences. APE5137, APE5121, and other anti-TIM-3 antibodies are disclosed in WO 2016/161270, which is incorporated by reference in its entirety.

In one embodiment, the anti-TIM-3 antibody molecule is antibody clone F38-2E2. In one embodiment, the anti-TIM-3 antibody molecule comprises one or more (or collectively all CDR sequences) of the CDR sequences of F38-2E2, heavy or light chain variable region sequences, or heavy or light chain sequences.

Additional known anti-TIM-3 antibodies include, for example, those described in WO 2016/111947, WO 2016/071448, WO 2016/144803, US 8,552,156, US 8,841,418, and US 9,163,087, the entirety of which Incorporated by reference.

In one embodiment, the anti-TIM-3 antibody is an antibody that competes for and / or binds to one of the anti-TIM-3 antibodies described herein with the same epitope on TIM-3.

Table 8. Amino acid sequences of other exemplary anti-TIM-3 antibody molecules

GITR agonists

In certain embodiments, the anti-LAG-3 antibody molecules described herein are administered in combination with a GITR agonist. In some embodiments, the GITR agonist is GWN323 (NVS), BMS-986156, MK-4166 or MK-1248 (Merck), TRX518 (Leap Therapeutics), INCAGN1876 (Incyte / Agenus (Agenus)), AMG 228 (Amgen) or INBRX-110 (Inhibrx).

Exemplary GITR agonists

In one embodiment, the GITR agonist is an anti-GITR antibody molecule. In one embodiment, the GITR agonist is an anti-GITR antibody molecule as described under WO 2016/057846 published on April 14, 2016, "Compositions and Methods of Use for Enhanced Immune Response and Cancer Therapy", This is incorporated by reference in its entirety.

In one embodiment, the anti-GITR antibody molecule is from a heavy and light chain variable region comprising the amino acid sequences set forth in Table 9 (e.g., from the heavy and light chain variable region sequences of MAB7 set forth in Table 9), or a table. At least 1, 2, 3, 4, 5 or 6 complementarity determining regions (CDRs) (or collectively all CDRs) from those encoded by the nucleotide sequences set forth in 9. In some embodiments, CDRs are according to the Kabat definition (eg, as shown in Table 9). In some embodiments, CDRs are according to the Chothia definition (eg, as shown in Table 9). In one embodiment, one or more (or collectively all CDRs) of the CDRs are 1, 2, 3, 4, 5, 6 compared to those encoded by the amino acid sequences set forth in Table 9, or the nucleotide sequences set forth in Table 9. Dog or more changes, eg, amino acid substitutions (eg, conservative amino acid substitutions) or deletions.

In one embodiment, the anti-GITR antibody molecule comprises a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO: 909, the VHCDR2 amino acid sequence of SEQ ID NO: 911, and the VHCDR3 amino acid sequence of SEQ ID NO: 913. ; And a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 914, the VLCDR2 amino acid sequence of SEQ ID NO: 916, and the VLCDR3 amino acid sequence of SEQ ID NO: 918, each of which is disclosed in Table 9 It is done.

In one embodiment, the anti-GITR antibody molecule comprises an amino acid sequence of SEQ ID NO: 901, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 901. VH. In one embodiment, the anti-GITR antibody molecule comprises an amino acid sequence of SEQ ID NO: 902, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 902. VL. In one embodiment, the anti-GITR antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 901 and a VL comprising the amino acid sequence of SEQ ID NO: 902.

In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 905, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 905. Includes. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 906, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 906. Includes. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 905 and a VL encoded by the nucleotide sequence of SEQ ID NO: 906.

In one embodiment, the anti-GITR antibody molecule comprises an amino acid sequence of SEQ ID NO: 903, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 903 Heavy chains. In one embodiment, the anti-GITR antibody molecule comprises an amino acid sequence of SEQ ID NO: 904, or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 904. Light chain. In one embodiment, the anti-GITR antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 903 and a light chain comprising the amino acid sequence of SEQ ID NO: 904.

In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 907, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 907. Includes. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 908, or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 908. Includes. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 907 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 908.

The antibody molecules described herein can be made by the vectors, host cells, and methods described in WO 2016/057846, which is incorporated by reference in its entirety.

Table 9: Amino acid and nucleotide sequences of exemplary anti-GITR antibody molecules

Other exemplary GITR agonists

In one embodiment, the anti-GITR antibody molecule is BMS-986156 (Bristol-Myers Squibb), also known as BMS 986156 or BMS986156. BMS-986156 and other anti-GITR antibodies are disclosed, for example, in US 9,228,016 and WO 2016/196792, which is incorporated by reference in its entirety. In one embodiment, the anti-GITR antibody molecule is, for example, one or more (or collectively all CDR sequences) of the CDR sequences of BMS-986156, as disclosed in Table 10, heavy or light chain variable region sequences, or Heavy chain or light chain sequence.

In one embodiment, the anti-GITR antibody molecule is MK-4166 or MK-1248 (Merck). MK-4166, MK-1248, and other anti-GITR antibodies are described, for example, in US 8,709,424, WO 2011/028683, WO 2015/026684, and Mahne et al. Cancer Res. 2017; 77 (5): 1108-1118, which is incorporated by reference in its entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more (or collectively all CDR sequences) of the CDR sequences of MK-4166 or MK-1248, heavy or light chain variable region sequences, or heavy or light chain sequences. .

In one embodiment, the anti-GITR antibody molecule is TRX518 (Lip Terrafutics). TRX518 and other anti-GITR antibodies are described, for example, in US 7,812,135, US 8,388,967, US 9,028,823, WO 2006/105021, and Ponte J et al. (2010) Clinical Immunology; 135: S96, the entire contents of which are incorporated by reference. In one embodiment, the anti-GITR antibody molecule comprises one or more (or collectively all CDR sequences) of the CDR sequences of TRX518, heavy or light chain variable region sequences, or heavy or light chain sequences.

In one embodiment, the anti-GITR antibody molecule is INCAGN1876 (Insight / Agenus). INCAGN1876 and other anti-GITR antibodies are disclosed, for example, in US 2015/0368349 and WO 2015/184099, which is incorporated by reference in its entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more (or collectively all CDR sequences) of the CDR sequences of INCAGN1876, heavy or light chain variable region sequences, or heavy or light chain sequences.

In one embodiment, the anti-GITR antibody molecule is AMG 228 (Amgen). AMG 228 and other anti-GITR antibodies are disclosed, for example, in US 9,464,139 and WO 2015/031667, which is incorporated by reference in its entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more (or collectively all CDR sequences) of the CDR sequences of AMG 228, heavy or light chain variable region sequences, or heavy or light chain sequences.

In one embodiment, the anti-GITR antibody molecule is INBRX-110 (Inhivx). INBRX-110 and other anti-GITR antibodies are disclosed, for example, in US 2017/0022284 and WO 2017/015623, which is incorporated by reference in its entirety. In one embodiment, the GITR agonist comprises one or more (or collectively all CDR sequences) of the CDR sequences of INBRX-110, heavy or light chain variable region sequences, or heavy or light chain sequences.

In one embodiment, the GITR agonist (eg, fusion protein) is MEDI 1873 (Medmund), also known as MEDI1873. MEDI 1873 and other GITR agonists are described, for example, in US 2017/0073386, WO 2017/025610, and Ross et al. Cancer Res 2016; 76 (14 Suppl): Abstract nr 561, which is incorporated by reference in its entirety. In one embodiment, the GITR agonist comprises one or more of the IgG Fc domain, functional multimerization domain, and receptor binding domain of the glucocorticoid-derived TNF receptor ligand (GITRL) of MEDI 1873.

Additional known GITR agonists (eg, anti-GITR antibodies) include, for example, those described in WO 2016/054638, which is incorporated by reference in its entirety.

In one embodiment, an anti-GITR antibody is an antibody that competes for and / or binds to one of the anti-GITR antibodies described herein with the same epitope on GITR.

In one embodiment, the GITR agonist is a peptide that activates the GITR signaling pathway. In one embodiment, the GITR agonist is an immunoadhesin binding fragment fused to a constant region (e.g., an Fc region of an immunoglobulin sequence) (e.g., comprising an extracellular or GITR binding portion of GITRL). Munoadhesin binding fragment).

Table 10: Amino acid sequence of other exemplary anti-GITR antibody molecules

IL15 / IL-15Ra complex

In certain embodiments, the anti-LAG-3 antibody molecules described herein are administered in combination with an IL-15 / IL-15Ra complex. In some embodiments, the IL-15 / IL-15Ra complex is selected from NIZ985 (Nopartis), ATL-803 (Altor) or CYP0150 (Cytune).

Exemplary IL-15 / IL-15Ra complex

In one embodiment, the IL-15 / IL-15Ra complex comprises human IL-15 complexed with a soluble form of human IL-15Ra. The complex may include IL-15, covalently or non-covalently bound to the soluble form of IL-15Ra. In certain embodiments, human IL-15 is non-covalently bound to the soluble form of IL-15Ra. In certain embodiments, the human IL-15 of the composition comprises the amino acid sequence of SEQ ID NO: 1001 in Table 11, and the soluble form of human IL-15Ra is as described in WO 2014/066527, incorporated herein by reference in its entirety. Likewise, the amino acid sequence of SEQ ID NO: 1002 of Table 11 is included. The molecules described herein can be made by the vectors, host cells, and methods described in WO 2007/084342, which is incorporated by reference in its entirety.

Table 11. Amino acid and nucleotide sequences of exemplary IL-15 / IL-15Ra complexes

Other exemplary IL-15 / IL-15Ra complexes

In one embodiment, the IL-15 / IL-15Ra complex is ALT-803, an IL-15 / IL-15Ra Fc fusion protein (IL-15N72D: IL-15RaSu / Fc soluble complex). ALT-803 is disclosed in WO 2008/143794, which is incorporated by reference in its entirety. In one embodiment, the IL-15 / IL-15Ra Fc fusion protein comprises the sequences as set forth in Table 12.

In one embodiment, the IL-15 / IL-15Ra complex comprises IL-15 fused to the sushi domain of IL-15Ra (CYP0150, Cytune). The sushi domain of IL-15Ra refers to the domain that starts at the first cysteine residue after the signal peptide of IL-15Ra and ends at the fourth cysteine residue after the signal peptide. Complexes of IL-15 fused to the sushi domain of IL-15Ra are disclosed in WO 2007/04606 and WO 2012/175222, the entire contents of which are incorporated by reference. In one embodiment, IL-15 / IL-15Ra sushi domain fusion comprises the sequences as set forth in Table 12.

Table 12. Amino acid sequences of other exemplary IL-15 / IL-15Ra complexes

Pharmaceutical compositions, formulations, and kits

In another aspect, the disclosure provides a composition, for example a pharmaceutically acceptable composition comprising an anti-LAG-3 antibody molecule described herein, formulated with a pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable carrier” includes any and all solvents that are physiologically compatible, dispersion media, isotonic and absorption delaying agents, and the like. The carrier may be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (eg by injection or infusion).

The compositions described herein can be in various forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (eg, injectable and injectable solutions), dispersions or suspensions, liposomes and suppositories. The preferred form depends on the intended mode of administration and therapeutic use. Typical preferred compositions are in the form of injectable or injectable solutions. The preferred mode of administration is parenteral (eg, intravenous, subcutaneous, intraperitoneal, intramuscular). In a preferred embodiment, the antibody is administered by intravenous infusion or injection. In another preferred embodiment, the antibody is administered by intramuscular or subcutaneous injection.

As used herein, the phrases “parenteral administration” and “administered parenterally” refer to modes of administration other than enteral and topical administration, typically by injection, but are not limited to intravenous, intramuscular, intraarterial, spinal cavity. Intradermal, intradermal, orbital, intracardiac, intradermal, intraperitoneal, cervical, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intrathecal, intradural and intrasternal injections and infusions.

The therapeutic composition should typically be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable for high antibody concentration. Sterile injectable solutions are prepared by incorporating the required amount of the active compound (e.g., antibody or antibody portion) in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. You can. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and other ingredients required from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is vacuum drying and freeze-drying to produce a powder of the active ingredient plus any additional desired ingredients from its previously sterile-filtered solution. The proper fluidity of the solution can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants. Sustained absorption of injectable compositions can occur by including in the composition an agent that delays absorption, such as monostearate salts and gelatin.

The anti-LAG-3 antibody molecule or composition described herein can be formulated into an agent (eg, a dosage form or dosage form) suitable for administration (eg, intravenous administration) to a subject as described herein. The formulations described herein can be liquid formulations, lyophilized formulations, or reconstituted formulations.

In certain embodiments, the formulation is a liquid formulation. In some embodiments, the formulation (eg, liquid formulation) comprises an anti-LAG-3 antibody molecule (eg, an anti-LAG-3 antibody molecule described herein) and a buffer.

In some embodiments, the formulation (e.g., liquid formulation) is 25 mg / mL to 250 mg / mL, e.g., 50 mg / mL to 200 mg / mL, 60 mg / mL to 180 mg / mL, 70 mg / mL to 150 mg / mL, 80 mg / mL to 120 mg / mL, 90 mg / mL to 110 mg / mL, 50 mg / mL to 150 mg / mL, 50 mg / mL to 100 mg / mL, 150 mg / mL to 200 mg / mL, or 100 mg / mL to 200 mg / mL, e.g. 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 anti-LAG-3 antibody molecules present at concentrations of mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, or 150 mg / mL. In certain embodiments, the anti-LAG-3 antibody molecule is present at a concentration of 80 mg / mL to 120 mg / mL, for example 100 mg / mL.

In some embodiments, the formulation (eg, liquid formulation) comprises a buffer that includes histidine (eg, histidine buffer). In certain embodiments, the buffer (e.g., histidine buffer) is 1 mM to 100 mM, e.g., 2 mM to 50 mM, 5 mM to 40 mM, 10 mM to 30 mM, 15 to 25 mM, 5 mM To 40 mM, 5 mM to 30 mM, 5 mM to 20 mM, 5 mM to 10 mM, 40 mM to 50 mM, 30 mM to 50 mM, 20 mM to 50 mM, 10 mM to 50 mM, or 5 mM to Present at a concentration of 50 mM, eg 2 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, or 50 mM. In some embodiments, the buffer (eg, histidine buffer) is present at a concentration of 15 mM to 25 mM, eg, 20 mM. In other embodiments, the buffer (eg, histidine buffer) has a pH of 4 to 7, eg, 5 to 6, eg, 5, 5.5, or 6. In some embodiments, the buffer (eg, histidine buffer) has a pH of 5 to 6, eg 5.5. In certain embodiments, the buffer comprises a histidine buffer at a concentration of 15 mM to 25 mM (eg, 20 mM) and has a pH of 5 to 6 (eg, 5.5). In certain embodiments, the buffering agent includes histidine and histidine-HCl.

In some embodiments, the formulation (eg, liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 80 to 120 mg / mL, eg, 100 mg / mL; And a histidine buffer at a concentration of 15 mM to 25 mM (eg, 20 mM) and a buffer having a pH of 5 to 6 (eg, 5.5).

In some embodiments, the formulation (eg, liquid formulation) further comprises carbohydrates. In certain embodiments, the carbohydrate is sucrose. In some embodiments, the carbohydrate (eg, sucrose) is 50 mM to 500 mM, eg, 100 mM to 400 mM, 150 mM to 300 mM, 180 mM to 250 mM, 200 mM to 240 mM, 210 mM to 230 mM, 100 mM to 300 mM, 100 mM to 250 mM, 100 mM to 200 mM, 100 mM to 150 mM, 300 mM to 400 mM, 200 mM to 400 mM, or 100 mM to 400 mM, e.g. For example, it is present at a concentration of 100 mM, 150 mM, 180 mM, 200 mM, 220 mM, 250 mM, 300 mM, 350 mM, or 400 mM. In some embodiments, the formulation comprises carbohydrate or sucrose present at a concentration of 200 mM to 250 mM, eg, 220 mM.

In some embodiments, the formulation (eg, liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 80 to 120 mg / mL, eg, 100 mg / mL; A buffer comprising a histidine buffer at a concentration of 15 mM to 25 mM (eg, 20 mM) and a pH of 5 to 6 (eg, 5.5); And carbohydrates or sucrose present at a concentration of 200 mM to 250 mM, eg, 220 mM.

In some embodiments, the formulation (eg, liquid formulation) further comprises a surfactant. In certain embodiments, the surfactant is polysorbate 20. In some embodiments, the surfactant or polysorbate 20 is 0.005% to 0.1% (w / w), e.g., 0.01% to 0.08%, 0.02% to 0.06%, 0.03% to 0.05%, 0.01% to 0.06 %, 0.01% to 0.05%, 0.01% to 0.03%, 0.06% to 0.08%, 0.04% to 0.08%, or 0.02% to 0.08% (w / w), e.g., 0.01%, 0.02%, 0.03% , 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1% (w / w). In some embodiments, the formulation comprises surfactant or polysorbate 20 present at a concentration of 0.03% to 0.05%, for example 0.04% (w / w).

In some embodiments, the formulation (eg, liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 80 to 120 mg / mL, eg, 100 mg / mL; A buffer comprising a histidine buffer at a concentration of 15 mM to 25 mM (eg, 20 mM) and a pH of 5 to 6 (eg, 5.5); Carbohydrate or sucrose present at a concentration of 200 mM to 250 mM, eg, 220 mM; And surfactant or polysorbate 20 present in a concentration of 0.03% to 0.05%, for example 0.04% (w / w).

In some embodiments, the formulation (eg, liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 100 mg / mL; A buffer containing a histidine buffer at a concentration of 20 mM (eg, histidine / histidine-HCL) and a pH of 5.5; Carbohydrate or sucrose present at a concentration of 220 mM; And surfactant or polysorbate 20 present at a concentration of 0.04% (w / w).

In some embodiments, liquid formulations are prepared by diluting formulations comprising anti-LAG-3 antibody molecules described herein. For example, a drug substance formulation can be diluted with a solution comprising one or more excipients (eg, concentrated excipients). In some embodiments, the solution comprises one, two, or all of histidine, sucrose, or polysorbate 20. In certain embodiments, the solution comprises the same excipient (s) as the drug substance formulation. Exemplary excipients include, but are not limited to, amino acids (eg, histidine), carbohydrates (eg, sucrose), or surfactants (eg, polysorbate 20). In certain embodiments, the liquid formulation is not a reconstituted lyophilized formulation. In other embodiments, the liquid formulation is a reconstituted lyophilized formulation. In some embodiments, the formulation is stored as a liquid. In other embodiments, the formulation is prepared as a liquid and then dried prior to storage, for example by lyophilization or spray-drying.

In certain embodiments, 0.5 mL to 10 mL (eg, 0.5 mL to 8 mL, 1 mL to 6 mL, or 2 mL to 5 mL, such as 1 mL, 1.2 mL, 1.5 mL, 2 mL, 3 mL, 4 mL, 4.5 mL, or 5 mL) of liquid preparation is charged into a container (eg, a vial). In other embodiments, the liquid formulation comprises at least 1 mL (e.g., at least 1.2 mL, at least 1.5 mL, at least 2 mL, at least 3 mL, at least 4 mL, or at least 1 mL of liquid preparation per container (e.g., vial). 5 mL) is filled into a container (eg, a vial) so that an extractable volume can be taken out. In certain embodiments, the liquid formulation is extracted from the container (eg, vial) without dilution at the clinical site. In certain embodiments, the liquid formulation is diluted from a drug substance formulation in the clinical setting and extracted from a container (eg, a vial). In certain embodiments, the formulation (e.g., liquid formulation) is placed in an infusion bag prior to initiation of infusion into a patient, e.g., within 1 hour (e.g., within 45, 30, or 15 minutes). Is injected.

The formulations described herein can be stored in containers. Containers used for any of the formulations described herein can include, for example, vials, and optionally stoppers, caps, or both. In certain embodiments, the vial is a glass vial, for example a 6R white glass vial. In other embodiments, the stopper is a rubber stopper, for example a gray rubber stopper. In other embodiments, the cap is a flip-off cap, such as an aluminum flip-off cap. In some embodiments, the container includes a 6R white glass vial, a gray rubber stopper and an aluminum flip-off cap. In some embodiments, a container (eg, vial) is for a single-use container. In certain embodiments, 25 mg / mL to 250 mg / mL, for example 50 mg / mL to 200 mg / mL, 60 mg / mL to 180 mg / mL, 70 mg / mL to 150 mg / mL, 80 mg / mL to 120 mg / mL, 90 mg / mL to 110 mg / mL, 50 mg / mL to 150 mg / mL, 50 mg / mL to 100 mg / mL, 150 mg / mL to 200 mg / mL, or 100 mg / mL to 200 mg / mL, e.g. 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 An anti-LAG-3 antibody molecule at mg / mL, 130 mg / mL, 140 mg / mL, or 150 mg / mL is present in a container (eg, a vial).

In some embodiments, the formulation is a lyophilized formulation. In certain embodiments, the lyophilized formulation is lyophilized or dried from a liquid formulation comprising an anti-LAG-3 antibody molecule described herein. For example, 1 to 5 mL, for example, 1 to 2 mL of liquid preparation can be filled per container (eg, a vial) and lyophilized.

In some embodiments, the formulation is a reconstituted formulation. In certain embodiments, the reconstituted agent is reconstituted from a lyophilized agent comprising an anti-LAG-3 antibody molecule described herein. For example, a reconstituted formulation can be prepared by dissolving the lyophilized formulation in a diluent so that the protein is dispersed in the reconstituted formulation. In some embodiments, the lyophilized formulation is reconstituted with 1 mL to 5 mL, eg, 1 mL to 2 mL, eg, 1.2 mL of water for injection or buffer. In certain embodiments, the lyophilized formulation is reconstituted with, for example, 1 mL to 2 mL of water for injection in a clinical setting.

In some embodiments, the reconstituted agent comprises an anti-LAG-3 antibody molecule (eg, an anti-LAG-3 antibody molecule described herein) and a buffer.

In some embodiments, the reconstituted formulation is 25 mg / mL to 250 mg / mL, for example 50 mg / mL to 200 mg / mL, 60 mg / mL to 180 mg / mL, 70 mg / mL to 150 mg / mL, 80 mg / mL to 120 mg / mL, 90 mg / mL to 110 mg / mL, 50 mg / mL to 150 mg / mL, 50 mg / mL to 100 mg / mL, 150 mg / mL to 200 mg / mL, or 100 mg / mL to 200 mg / mL, e.g., 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, or anti-LAG-3 antibody molecule present at a concentration of 150 mg / mL. In certain embodiments, the anti-LAG-3 antibody molecule is present at a concentration of 80 mg / mL to 120 mg / mL, for example 100 mg / mL.

In some embodiments, the reconstituted formulation comprises a buffer comprising histidine (eg, histidine buffer). In certain embodiments, the buffer (e.g., histidine buffer) is 1 mM to 100 mM, e.g., 2 mM to 50 mM, 5 mM to 40 mM, 10 mM to 30 mM, 15 to 25 mM, 5 mM To 40 mM, 5 mM to 30 mM, 5 mM to 20 mM, 5 mM to 10 mM, 40 mM to 50 mM, 30 mM to 50 mM, 20 mM to 50 mM, 10 mM to 50 mM, or 5 mM to Present at a concentration of 50 mM, eg 2 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, or 50 mM. In some embodiments, the buffer (eg, histidine buffer) is present at a concentration of 15 mM to 25 mM, eg, 20 mM. In other embodiments, the buffer (eg, histidine buffer) has a pH of 4 to 7, eg, 5 to 6, eg, 5, 5.5, or 6. In some embodiments, the buffer (eg, histidine buffer) has a pH of 5 to 6, eg 5.5. In certain embodiments, the buffer comprises a histidine buffer at a concentration of 15 mM to 25 mM (eg, 20 mM) and has a pH of 5 to 6 (eg, 5.5). In certain embodiments, the buffering agent includes histidine and histidine-HCl.

In some embodiments, the reconstituted agent comprises an anti-LAG-3 antibody molecule present at a concentration of 80 to 120 mg / mL, eg, 100 mg / mL; And a histidine buffer at a concentration of 15 mM to 25 mM (eg, 20 mM) and a buffer having a pH of 5 to 6 (eg, 5.5).

In some embodiments, the reconstituted formulation further comprises carbohydrates. In certain embodiments, the carbohydrate is sucrose. In some embodiments, the carbohydrate (eg, sucrose) is 50 mM to 500 mM, eg, 100 mM to 400 mM, 150 mM to 300 mM, 180 mM to 250 mM, 200 mM to 240 mM, 210 mM to 230 mM, 100 mM to 300 mM, 100 mM to 250 mM, 100 mM to 200 mM, 100 mM to 150 mM, 300 mM to 400 mM, 200 mM to 400 mM, or 100 mM to 400 mM, e.g. For example, it is present at a concentration of 100 mM, 150 mM, 180 mM, 200 mM, 220 mM, 250 mM, 300 mM, 350 mM, or 400 mM. In some embodiments, the formulation comprises carbohydrate or sucrose present at a concentration of 200 mM to 250 mM, eg, 220 mM.

In some embodiments, the reconstituted agent comprises an anti-LAG-3 antibody molecule present at a concentration of 80 to 120 mg / mL, eg, 100 mg / mL; A buffer comprising a histidine buffer at a concentration of 15 mM to 25 mM (eg, 20 mM) and a pH of 5 to 6 (eg, 5.5); And carbohydrates or sucrose present at a concentration of 200 mM to 250 mM, eg, 220 mM.

In some embodiments, the reconstituted formulation further comprises a surfactant. In certain embodiments, the surfactant is polysorbate 20. In some embodiments, the surfactant or polysorbate 20 is 0.005% to 0.1% (w / w), e.g., 0.01% to 0.08%, 0.02% to 0.06%, 0.03% to 0.05%, 0.01% to 0.06 %, 0.01% to 0.05%, 0.01% to 0.03%, 0.06% to 0.08%, 0.04% to 0.08%, or 0.02% to 0.08% (w / w), e.g., 0.01%, 0.02%, 0.03% , 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1% (w / w). In some embodiments, the formulation comprises surfactant or polysorbate 20 present at a concentration of 0.03% to 0.05%, for example 0.04% (w / w).

In some embodiments, the reconstituted agent comprises an anti-LAG-3 antibody molecule present at a concentration of 80 to 120 mg / mL, eg, 100 mg / mL; A buffer comprising a histidine buffer at a concentration of 15 mM to 25 mM (eg, 20 mM) and a pH of 5 to 6 (eg, 5.5); Carbohydrate or sucrose present at a concentration of 200 mM to 250 mM, eg, 220 mM; And surfactant or polysorbate 20 present in a concentration of 0.03% to 0.05%, for example 0.04% (w / w).

In some embodiments, the reconstituted agent is an anti-LAG-3 antibody molecule present at a concentration of 100 mg / mL; A buffer containing a histidine buffer at a concentration of 20 mM (eg, histidine / histidine-HCL) and a pH of 5.5; Carbohydrate or sucrose present at a concentration of 220 mM; And surfactant or polysorbate 20 present at a concentration of 0.04% (w / w).

In some embodiments, the formulation is at least 1 mL (eg, at least 1.2 mL, 1.5 mL, 2 mL, 2.5 mL, or 3 mL) of the reconstituted preparation from a container (eg, a vial) containing the reconstituted preparation. ) So that the extractable volume can be taken out. In certain embodiments, the formulation is reconstituted in the clinical setting and / or extracted from a container (eg, vial). In certain embodiments, the formulation (e.g., reconstituted formulation) is injected into the patient prior to infusion, e.g., within 1 hour (e.g., within 45 minutes, 30 minutes, or 15 minutes). Is injected into.

Other exemplary buffers that can be used in the formulations described herein include, but are not limited to, arginine buffers, citrate buffers or phosphate buffers. Other exemplary carbohydrates that can be used in the formulations described herein include, but are not limited to, trehalose, mannitol, sorbitol, or combinations thereof. The formulations described herein may also contain isotonic agents, such as sodium chloride, and / or stabilizers, such as amino acids (eg, glycine, arginine, methionine, or combinations thereof).

Antibody molecules can be administered by a variety of methods known in the art, but for many therapeutic uses, the preferred route / mode of administration is intravenous injection or infusion. For example, the antibody molecule is administered at a rate greater than 20 mg / min, for example 20-40 mg / min, and typically at least 40 mg / min by intravenous infusion, such that about 35 to 440 mg / m ² , Doses typically range from about 70 to 310 mg / m ² , and more typically from about 110 to 130 mg / m ² . In an embodiment, the antibody molecule has a dose of about 1 to 100 mg / m ² , preferably about 5 to 50 mg / m ² , about 7 to 25 mg / m ² and more preferably about 10 mg / m ² Less than 10 mg / min by intravenous infusion to reach; Preferably, it can be administered at a rate of 5 mg / min or less. As will be appreciated by the skilled artisan, the route and / or mode of administration will vary depending on the desired outcome. In certain embodiments, the active compounds can be prepared with controlled release agents, including implants, transdermal patches, and microencapsulated delivery systems, using a carrier that will protect the compound against rapid release. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Many methods for the preparation of such formulations have been patented or are generally known to those skilled in the art. See, for example, Sustained and Controlled Release Drug Delivery Systems, JR Robinson, ed., Marcel Dekker, Inc., New York, 1978.

In certain embodiments, the antibody molecule can be administered orally, for example, by an inert diluent or an anabolic edible carrier. The compounds (and other ingredients, if desired) can also be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the subject's diet. For oral therapeutic administration, the compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. In order to administer a compound of the invention other than parenteral administration, it may be necessary to coat the compound with a substance that prevents its inactivation or co-administer the compound with such a substance. The therapeutic composition can be administered by medical devices known in the art.

The dosing regimen is adjusted to provide the optimal desired response (eg, therapeutic response). For example, a single bolus can be administered, multiple divided doses can be administered over time, or the dose can be reduced or increased proportionally as indicated by the urgency of the treatment situation. It is particularly advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; Each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Details regarding the dosage unit form of the present invention include (a) the unique characteristics of the active compound and the specific therapeutic effect to be achieved, and (b) the limitations present in the art of combining these active compounds for susceptible treatment in an individual. Directed by, and directly dependent on, matters.

An exemplary, non-limiting range for therapeutic or prophylactically effective amounts of antibody molecules is 50 mg to 1500 mg, typically 80 mg to 1200 mg. In certain embodiments, the anti-LAG-3 antibody molecule is about 60 mg to about 100 mg (e.g., about 80 mg), about 200 mg to about 300 by injection (e.g., subcutaneously or intravenously). mg (eg, about 240 mg), or about 1000 mg to about 1500 mg (eg, about 1200 mg) at a dose (eg, uniform dose). The dosing schedule (eg, uniform dosing schedule) can vary, for example, once a week to once every 2, 3, 4, 5 or 6 weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered once every two weeks or once every four weeks at a dose of about 60 mg to 100 mg (e.g., about 80 mg). In one embodiment, the anti-LAG-3 antibody molecule is administered once every 2 weeks or once every 4 weeks at a dose of about 200 mg to about 300 mg (eg, about 240 mg). In one embodiment, the anti-LAG-3 antibody molecule is administered at a dose of about 1000 mg to about 1500 mg (eg, about 1200 mg) once every 2 weeks or once every 4 weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered once every 4 weeks at a dose of about 80 mg. In one embodiment, the anti-LAG-3 antibody molecule is administered once every 4 weeks at a dose of about 240 mg. In one embodiment, the anti-LAG-3 antibody molecule is administered once every 4 weeks at a dose of about 1200 mg. While not wishing to be bound by theory, uniform or fixed administration may be beneficial to the patient in some embodiments, for example, to conserve drug supply and reduce pharmaceutical errors.

The antibody molecule is 20 mg / min by intravenous infusion to reach a dose of about 35 to 440 mg / m ² , typically about 70 to 310 mg / m ² , more typically about 110 to 130 mg / m ² Greater than, for example, 20-40 mg / min, generally at a rate of 40 mg / min or greater. In an embodiment, an infusion rate of about 110 to 130 mg / m ² achieves a level of about 3 mg / kg. In other embodiments, the antibody molecule reaches a dose of about 1 to 100 mg / m ² , for example about 5 to 50 mg / m ² , about 7 to 25 mg / m ² , or about 10 mg / m ² For less than 10 mg / min, for example 5 mg / min or less, it can be administered by intravenous infusion. In some embodiments, the antibody is injected over a period of about 30 minutes. It should be noted that the dose value may vary depending on the type and severity of the condition to be alleviated. Additionally, for any particular subject, the specific dosing regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or administering the composition, and the dosage ranges presented herein are It should be understood that it is merely exemplary and is not intended to limit the scope or practice of the claimed composition.

The pharmaceutical composition of the present invention may include a "therapeutically effective amount" or "prophylactically effective amount" of the antibody or antibody portion of the present invention. “Therapeutically effective amount” refers to an amount effective to achieve this at the dosage and duration necessary to achieve the desired therapeutic result. The therapeutically effective amount of a modified antibody or antibody fragment can vary depending on factors such as the subject's disease state, age, sex and body weight, and the ability of the antibody or antibody portion to elicit the desired response in the individual. A therapeutically effective amount also has a greater therapeutically beneficial effect than any toxic or detrimental effect of the modified antibody or antibody fragment. A “therapeutically effective dose” is preferably a measurable parameter, such as a tumor growth rate of at least about 20%, more preferably of at least about 40%, even more preferably of at least about 60 compared to an untreated subject. %, Even more preferably at least about 80%. Measurable parameters, such as the ability of compounds to inhibit cancer, can be assessed in animal model systems that can predict efficacy in human tumors. Alternatively, this property of the composition can be assessed by examining the ability of the compound to inhibit this inhibition in vitro by assays known to skilled practitioners.

“Prophylactically effective amount” refers to an amount effective to achieve this at the dosage and duration necessary to achieve the desired preventive result. Typically, the prophylactically effective amount will be less than the therapeutically effective amount since the prophylactic dose is used in the subject prior to or at an earlier stage of the disease.

In addition, kits comprising anti-LAG-3 antibody molecules, compositions, or agents described herein are within the scope of the disclosure. The kit can include one or more other elements, including: instructions for use (eg, according to the dosing regimen described herein); Other reagents, such as an agent for a label, therapeutic agent, or agent useful for chelating or otherwise coupling, an antibody to the label or therapeutic agent, or a radioprotective composition; Devices or other materials for making antibodies for administration; Pharmaceutically acceptable carriers; And devices or other substances for administration to a subject.

Use of anti-LAG-3 antibody molecules

The anti-LAG-3 antibody molecules described herein can be used to modify the immune response in a subject. In some embodiments, the immune response is enhanced, stimulated or up-regulated. In certain embodiments, the immune response is inhibited, reduced, or down-regulated. For example, these antibody molecules are administered to cells in culture, e.g., in vitro or ex vivo, to treat, prevent, and / or diagnose various disorders, such as cancer, immune disorders, and infectious diseases, or The subject can be administered, for example, in vivo.

The term “subject” as used herein is intended to include human and non-human animals. In some embodiments, the subject is a human subject having a disorder or condition characterized by abnormal LAG-3 function, eg, a human patient. Generally, a subject has at least a portion of a LAG-3 protein, including a LAG-3 epitope bound by an antibody molecule, such as a sufficiently high level of protein and epitope to support antibody binding to LAG-3. The term "non-human animal" includes mammals and non-mammals, such as non-human primates. In some embodiments, the subject is a human. In some embodiments, the subject is a human patient in need of enhancing the immune response. The methods and compositions described herein are suitable for treating human patients with disorders that can be treated by modulating (e.g., enhancing or inhibiting) the immune response. In certain embodiments, the patient has or is at risk of having a disorder described herein, such as breast cancer, such as triple negative breast cancer (TNBC). In certain embodiments, patients with TNBC are more immunogenic than other breast cancer subtypes and / or have higher PD-L1 expression and / or increased infiltration by tumor-infiltrating lymphocytes (TIL) (Loi et. al. (2014) Ann Oncol; 25: 1544-50; Mittendorf et al. (2014) Cancer Immunol Res; 2: 361-70). In one embodiment, the patient does not exhibit liver metastasis.

Combination immunotherapy approaches suggest that synergistic blockade of co-inhibiting receptors demonstrates greater antitumor activity than single agents (Wolchok et al. (2013) New Engl J Med; 369: 122-33). LAG-3 is a co-inhibiting receptor capable of inhibiting the immune response in cooperation with PD-1 (Anderson et al. (2016) Immunity; 44: 989-1004). Inhibition of the combination of PD-1 and LAG-3 checkpoints synergistically enhances the anti-tumor response compared to inhibition of either checkpoint alone (Woo et al. (2012) Cancer Res; 72: 917-27) .

In addition, there is increasing evidence that cytotoxic agents affect the tumor-host environment, making them more beneficial to the immune response, and therefore, the combination of immunotherapy and cytotoxic agents may be synergistic to increase therapeutic efficacy (Zitvogel et. al. (2013) Immunity; 39: 74-88). Importantly, chemotherapy can induce immunogenic cell death, which promotes efficient antigen presentation and has been suggested to trigger strong T cell responses in preclinical models (Kroemer et al. (2013) Immunol; 31:51 -72; Pfirschke et al. (2016) Immunity; 44: 343-54; Lu et al. (2017) Biomedical Res; 28: 828-34). Without wishing to be bound by theory, in some embodiments, chemotherapy (eg, a platinum agent) will create an initial environment during T cell activation (eg, increased antigen concentration and / or antigen availability). This would favor the development of LAG-3 + CD8 + T cells, which is believed to require only LAG3 inhibition for differentiation into tumor antigen specific effector cells. Although the main mechanism of action of platinum agents is believed to be the induction of cancer cell apoptosis as a response of its covalent binding to DNA, recent studies have shown that cell molecules other than DNA can potentially act as targets, and antitumor effects of platinum drugs It has been suggested that some of these occur through the adjustment of the immune system (Hato et al. (2014) Clin Cancer Res; 20: 2831-7). These immunogenic effects include modulating STAT signaling (Lesterhuis et al. (2011) J Clin Invest; 121: 3100-08); Induction of cancer cell death of an immunogenic type through exposure of caleticulin and release of ATP and the high-mobility group protein box-1 (HMGB-1) (Kroemer et al. (2013) Immunol; 31: 51-72; Tesniere et al. (2010) Oncogenel; 29: 482-91); And enhancement of effector immune responses through modulation of programmed death receptor 1-ligand and mannose-6-phosphate receptor expression (Liu et al. (2010) Br J Cancer; 102: 115-23). Without wishing to be bound by theory, in some embodiments, combining platinum with immune checkpoint blocking can provide platinum to immunogenic cell death, tumor cell sensitization to CTL lysis, and down-regulation of PD-L. In this regard, it is believed to enhance immunotherapy.

In some embodiments, the subject has not been treated with a therapeutic agent, procedure or modality prior to receiving the anti-LAG-3 antibody molecule. In other embodiments, the subject has been treated with a therapeutic agent, procedure or modality prior to receiving an anti-LAG-3 antibody molecule.

In certain embodiments, the subject has not been treated with anti-LAG-3 therapy prior to receiving the anti-LAG-3 antibody molecule. In another embodiment, the subject has been treated with anti-LAG-3 therapy prior to receiving the anti-LAG-3 antibody molecule.

In certain embodiments, the subject has not been treated with PD-1 / PD-L1 therapy prior to receiving anti-LAG-3 antibody molecules. In another embodiment, the subject was treated with PD-1 / PD-L1 therapy prior to receiving the anti-LAG-3 antibody molecule.

In certain embodiments, the subject is given a chemotherapeutic agent (e.g., a platinum agent (e.g. carboplatin, cisplatin, oxaliplatin, or tetraplatin)) or a nucleotide analog prior to receiving an anti-LAG-3 antibody molecule or Not treated with precursor analogs (eg, capecitabine). In another embodiment, the subject is given a chemotherapeutic agent (e.g., a platinum agent (e.g. carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide analog) prior to receiving an anti-LAG-3 antibody molecule or Treated with precursor analogs (eg, capecitabine).

In certain embodiments, the subject has been identified as having LAG-3 expression in tumor infiltrating lymphocytes. In other embodiments, the subject does not have detectable levels of LAG-3 expression in tumor infiltrating lymphocytes.

How to treat cancer

In one aspect, the disclosure includes an anti-LAG-3 antibody molecule (eg, an anti-LAG-3 antibody molecule described herein) or an anti-LAG-3 antibody molecule such that growth of a cancerous tumor is inhibited or reduced. It relates to in vivo treatment of a subject using a composition or formulation (eg, a composition or formulation described herein).

In certain embodiments, the anti-LAG-3 antibody molecule is administered in an amount effective to treat cancer or metastatic lesions thereof. In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 100 mg to about 2000 mg once every 2 weeks, once every 3 weeks, or once every 4 weeks. For example, the anti-LAG-3 antibody molecule may be from about 200 mg to about 1000 mg, from about 300 mg to about 900 mg, from about 200 mg to about 600 mg, from about 300 mg to about 500 mg, from about 600 to about 1000 mg , About 700 mg to about 900 mg, or about 400 mg to about 800 mg, may be administered once every 3 weeks or once every 4 weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to 500 mg (eg, about 400 mg). In one embodiment, the anti-LAG-3 antibody molecule is administered once every 4 weeks at a dose of about 700 mg to about 900 mg (eg, about 800 mg). In one embodiment, the anti-LAG-3 antibody molecule is administered once every 4 weeks at a dose of about 500 mg to about 700 mg (eg, about 533 mg or about 600 mg).

Anti-LAG-3 antibodies, or compositions or formulations comprising anti-LAG-3 antibody molecules, can be used alone to inhibit the growth of cancerous tumors. Alternatively, an anti-LAG-3 antibody, or a composition or formulation comprising an anti-LAG-3 antibody molecule can be used in combination with one or more of the following: (e.g., for cancer or infectious disorders) Standard management therapy, another antibody or antigen-binding fragment thereof, an immunomodulator (eg, an activator of a costimulatory molecule or an inhibitor of an inhibitory molecule); Vaccines, eg, therapeutic cancer vaccines; Or other forms of cellular immunotherapy as described herein.

Thus, in one embodiment, the disclosure comprises administering to a subject a therapeutically effective amount of an anti-LAG-3 antibody molecule described herein, eg, in accordance with a dosing regimen described herein, growth of tumor cells in the subject. It provides a way to suppress. In one embodiment, the anti-LAG-3 antibody molecule is administered in the form of a composition or formulation described herein.

In one embodiment, the method is suitable for treatment of cancer in vivo. To achieve antigen-specific immunity enhancement, anti-LAG-3 antibody molecules can be administered with the antigen of interest. When the anti-LAG-3 antibody is administered in combination with one or more agents, the combination can be administered in either order or simultaneously.

In another aspect, a method of treating a subject, e.g., reducing or improving hyperproliferative condition or disorder (e.g., cancer) in a subject, e.g., solid tumor, blood cancer, soft tissue tumor, or metastatic lesion A method is provided. The methods include administering to a subject an anti-LAG-3 antibody molecule, or a composition or formulation comprising an anti-LAG-3 antibody molecule, as described herein, according to the dosing regimen disclosed herein.

As used herein, the term “cancer” is intended to include any type of cancerous growth or oncogenic process, metastatic tissue or cells, tissues, or organs that have been transformed to malignant, regardless of histopathological type or invasive stage. . Examples of cancerous disorders include, but are not limited to, solid tumors, blood cancers, soft tissue tumors, and metastatic lesions. Examples of solid tumors are malignancies of various organ systems, such as sarcomas and carcinomas (including adenocarcinomas and squamous cell carcinomas) such as liver, lung, breast, lymph, stomach (e.g. colon), urogenital tract (e.g. For example, those affecting the kidneys, urinary tract epithelium, bladder cells), prostate, CNS (eg, brain, nerve or glial cells), skin, pancreas, and pharynx. Adenocarcinomas include malignancies such as most colon cancer, rectal cancer, renal cell carcinoma, liver cancer, non-small cell carcinoma of the lung, small intestine cancer and esophageal cancer. Squamous cell carcinoma includes, for example, malignancies in the lungs, esophagus, skin, head and neck regions, oral cavity, anus and cervix. In one embodiment, the cancer is melanoma, eg, advanced stage melanoma. Metastatic lesions of the aforementioned cancers can also be treated or prevented using the methods and compositions of the invention.

Exemplary cancers whose growth can be inhibited using antibody molecules, compositions, or agents as disclosed herein typically include cancers that are reactive to immunotherapy. Non-limiting examples of typical cancers for treatment include melanoma (eg, metastatic malignant melanoma), renal cancer (eg, clear cell carcinoma), prostate cancer (eg, hormonal refractory prostate adenocarcinoma), breast cancer, Colon cancer and lung cancer (eg, non-small cell lung cancer). Additionally, refractory or recurrent malignancies can be treated using the antibody molecules described herein.

Examples of other cancers that can be treated include basal cell carcinoma, biliary tract cancer; Bladder cancer; Bone cancer; Brain and CNS cancer; Primary CNS lymphoma; Neoplasm of the central nervous system (CNS); Breast cancer; Cervical cancer; Chorionic carcinoma; Colon and rectal cancer; Connective tissue cancer; Digestive system cancer; Endometrial cancer; Esophageal cancer; Eye cancer; Head and neck cancer; Stomach cancer; Neoplasm in the epithelium; Kidney cancer; Laryngeal cancer; Leukemia (including acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic or acute leukemia); Liver cancer; Lung cancer (eg, small cells and non-small cells); Lymphomas including Hodgkin's lymphoma and non-Hodgkin's lymphoma; Lymphocytic lymphoma; Melanoma, eg, skin or intraocular malignant melanoma; Myeloma; Neuroblastoma; Oral cancer (eg, cleft lip, tongue, mouth, and pharynx); Ovarian cancer; Pancreatic cancer; Prostate cancer; Retinoblastoma; Rhabdomyosarcoma; Rectal cancer; Respiratory system cancer; sarcoma; cutaneous cancer; Stomach cancer; Testicular cancer; Thyroid cancer; Uterine cancer; Urinary system cancer, liver carcinoma, anal cancer, fallopian tube carcinoma, vaginal carcinoma, vulvar carcinoma, small intestine cancer, endocrine system cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, childhood solid tumor, spinal contraction tumor, brain stem Glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancer, including those caused by asbestos, as well as other carcinomas and sarcomas, and combinations of these cancers. , But is not limited thereto.

In some embodiments, the disorder is cancer, eg, a cancer described herein. In certain embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a brain tumor, eg, a glioblastoma, neuroeducation, or recurrent brain tumor. In some embodiments, the cancer is pancreatic cancer, eg, advanced pancreatic cancer. In some embodiments, the cancer is skin cancer, such as melanoma (eg, stage II-IV melanoma, HLA-A2 positive melanoma, unresectable melanoma, or metastatic melanoma), or Merkel cell carcinoma. . In some embodiments, the cancer is renal cancer, eg, renal cell carcinoma (RCC) (eg, metastatic renal cell carcinoma) or treatment-naive metastatic renal cancer. In some embodiments, the cancer is breast cancer, eg, metastatic breast carcinoma or stage IV breast carcinoma, such as triple negative breast cancer (TNBC). In some embodiments, the cancer is a virus-associated cancer. In some embodiments, the cancer is anal canal cancer (eg, squamous cell carcinoma of the anal canal). In some embodiments, the cancer is cervical cancer (eg, squamous cell carcinoma of the cervix). In some embodiments, the cancer is gastric cancer (eg, Epstein Barr virus (EBV) positive gastric cancer or gastric or gastro-esophageal junction carcinoma). In some embodiments, the cancer is head and neck cancer (eg, HPV positive and negative squamous cell head and neck cancer (SCCHN)). In some embodiments, the cancer is nasopharyngeal cancer (NPC). In some embodiments, the cancer is penile cancer (eg, squamous cell carcinoma of the penis). In some embodiments, the cancer is vaginal or vulvar cancer (eg, squamous cell carcinoma of the vagina or vulva). In some embodiments, the cancer is colorectal cancer, e.g., recurrent colorectal cancer or metastatic colorectal cancer, e.g., microsatellite unstable colorectal cancer, microsatellite stable colorectal cancer, mismatch recovery proficient colorectal cancer, or mismatch repair Deficient colorectal cancer. In some embodiments, the cancer is lung cancer, eg, non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is blood cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is a lymphoma, such as Hodgkin's lymphoma (HL) or diffuse versus B cell lymphoma (DLBCL) (eg, recurrent or refractory HL or DLBCL). In some embodiments, the cancer is myeloma. In some embodiments, the cancer is high-MSI cancer. In some embodiments, the cancer is metastatic cancer. In other embodiments, the cancer is advanced cancer. In other embodiments, the cancer is recurrent or refractory cancer.

In one embodiment, the cancer is Merkel cell carcinoma. In other embodiments, the cancer is melanoma. In other embodiments, the cancer is breast cancer, eg, triple negative breast cancer (TNBC) or HER2-negative breast cancer. In other embodiments, the cancer is renal cell carcinoma (eg, clear cell renal cell carcinoma (CCRCC) or non-transparent cell renal cell carcinoma (nccRCC)). In other embodiments, the cancer is thyroid cancer, eg, anaplastic thyroid carcinoma (ATC). In other embodiments, the cancer is a neuroendocrine tumor (NET), eg, atypical lung carcinoid tumor or pancreas, gastrointestinal (GI) tract, or NET in the lung. In certain embodiments, the cancer is non-small cell lung cancer (NSCLC) (eg, squamous NSCLC or non-squamous NSCLC). In certain embodiments, the cancer is fallopian tube cancer. In certain embodiments, the cancer is high-microsatellite unstable colorectal cancer (high-MSI CRC) or microsatellite stable colorectal cancer (MSS CRC).

In other embodiments, the cancer is a blood malignant tumor or cancer, including but not limited to leukemia or lymphoma. For example, the anti-LAG-3 antibody molecule can be, for example, acute leukemia, eg, B-cell acute lymphocytic leukemia (“BALL”), T-cell acute lymphocytic leukemia (“TALL”), Acute lymphocytic leukemia (ALL); Chronic leukemia, such as chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL); Additional blood cancers or blood conditions, such as B cell prelymphocytic leukemia, parental plasmacytoid dendritic cell neoplasm, Burkitt lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or Large cell-follicular lymphoma, malignant lymphoproliferative condition, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasia Treating cancer and malignancies, including but not limited to, "pre-leukemia", a diverse set of blood states associated by ineffective production (or dysplasia) such as living organisms, Waldenstrom macroglobulinemia, and bone marrow blood cells Can be used for

The term “subject” as used herein is intended to include human and non-human animals. In some embodiments, the subject is a human subject having a disorder or condition characterized by abnormal LAG-3 function, eg, a human patient. Generally, a subject has at least a portion of a LAG-3 protein, including a LAG-3 epitope bound by an antibody molecule, such as a sufficiently high level of protein and epitope to support antibody binding to LAG-3. The term "non-human animal" includes mammals and non-mammals, such as non-human primates. In some embodiments, the subject is a human. In some embodiments, the subject is a human patient in need of enhancing the immune response. The methods and compositions described herein are suitable for treating human patients with disorders that can be treated by modulating (e.g., enhancing or inhibiting) the immune response.

In some embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is administered as a single agent. In other embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is a second therapeutic agent or modality, such as a PD-1 inhibitor, PD-L1 inhibitor, or chemistry It is administered in combination with a therapeutic agent. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, eg, an anti-PD-1 antibody described herein. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, eg, an anti-PD-L1 antibody molecule described herein. In some embodiments, the chemotherapeutic agent is a platinum agent. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin. In certain embodiments, the platinum agent is oxaliplatin. In certain embodiments, the platinum agent is tetraplatin.

In some embodiments, the chemotherapeutic agent is a nucleotide analog or precursor analog. In certain embodiments, the nucleotide analog or precursor analog is capecitabine.

In certain embodiments, the cancer is a solid tumor. In some embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is administered as a single agent to treat a solid tumor. In other embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is a second therapeutic agent or modality for treating a solid tumor, such as a PD-1 inhibitor or PD -L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, eg, an anti-PD-1 antibody described herein. In certain embodiments, the anti-PD-1 antibody molecule is PDR001 (Spartalizumab). In certain embodiments, the anti-PD-1 antibody molecule is REGN2810. In other embodiments, the anti-PD-1 antibody molecule is nivolumab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, eg, an anti-PD-L1 antibody molecule described herein.

In certain embodiments, the cancer is breast cancer, eg, triple negative breast cancer (TNBC). In some embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is administered as a single agent to treat breast cancer (eg, TNBC). In other embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is a second therapeutic agent, e.g., PD-, for treating breast cancer (e.g., TNBC). 1 is administered in combination with an inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, eg, an anti-PD-1 antibody described herein. In certain embodiments, the anti-PD-1 antibody molecule is PDR001 (Spartalizumab). In certain embodiments, the anti-PD-1 antibody molecule is REGN2810. In other embodiments, the anti-PD-1 antibody molecule is nivolumab. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) to treat breast cancer (e.g., TNBC). And the PD-1 inhibitor is administered once every three weeks at a dose of about 200 mg to about 400 mg (eg, about 300 mg). In certain embodiments, an anti-LAG-3 antibody molecule (eg, an anti-LAG-3 antibody molecule described herein) for treating breast cancer (eg, TNBC) is from about 600 mg to about 1000 mg (eg For example, once every 4 weeks at a dose of about 800 mg, the PD-1 inhibitor (e.g., anti-PD-1 antibody molecule described herein) is from about 300 mg to about 500 mg (e.g. , About 400 mg) once every 4 weeks.

In certain embodiments, the cancer is breast cancer, eg, triple negative breast cancer (TNBC). In some embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is a second therapeutic agent, e.g., chemotherapy, to treat breast cancer (e.g., TNBC). It is administered in combination with a drug. In some embodiments, the chemotherapeutic agent is a platinum agent. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin. In certain embodiments, the platinum agent is oxaliplatin. In certain embodiments, the platinum agent is tetraplatin. In some embodiments, the chemotherapeutic agent is a nucleotide analog or precursor analog. In certain embodiments, the nucleotide analog or precursor analog is capecitabine. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) to treat breast cancer (e.g., TNBC). And the chemotherapeutic agent is administered once every three weeks at a dose to achieve an area under the curve (AUC) of about 4 to about 8 or about 5 to about 7 (eg, AUC of about 6).

In certain embodiments, the cancer is breast cancer, eg, triple negative breast cancer (TNBC). In some embodiments, an anti-LAG-3 antibody molecule, or a composition or formulation comprising an anti-LAG-3 antibody molecule, is combined with a PD-1 inhibitor and a chemotherapeutic agent to treat breast cancer (eg, TNBC) Is administered. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, eg, an anti-PD-1 antibody described herein. In certain embodiments, the anti-PD-1 antibody molecule is PDR001 (Spartalizumab). In certain embodiments, the anti-PD-1 antibody molecule is REGN2810. In other embodiments, the anti-PD-1 antibody molecule is nivolumab. In some embodiments, the chemotherapeutic agent is a platinum agent. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin. In certain embodiments, the platinum agent is oxaliplatin. In certain embodiments, the platinum agent is tetraplatin. In some embodiments, the chemotherapeutic agent is a nucleotide analog or precursor analog. In certain embodiments, the nucleotide analog or precursor analog is capecitabine. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) to treat breast cancer (e.g., TNBC). PD-1 inhibitor is administered once every three weeks at a dose of about 200 mg to about 400 mg (e.g., about 300 mg), and the chemotherapeutic agent is about 4 to about 8 or about 5 to about 7 It is administered once every three weeks at a dose to achieve AUC (eg, AUC of about 6).

In certain embodiments, the cancer is a brain tumor. In some embodiments, the brain tumor is glioblastoma (eg, recurrent glioblastoma). In some embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is administered as a single agent to treat brain tumors. In other embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is a second therapeutic agent or modality for treating a brain tumor, such as a PD-1 inhibitor or PD -L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, eg, an anti-PD-1 antibody described herein. In certain embodiments, the anti-PD-1 antibody molecule is PDR001 (Spartalizumab). In other embodiments, the anti-PD-1 antibody molecule is nivolumab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, eg, an anti-PD-L1 antibody molecule described herein.

In certain embodiments, the cancer is pancreatic cancer. In some embodiments, the pancreatic cancer is advanced pancreatic cancer. In some embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is administered as a single agent to treat pancreatic cancer. In other embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is administered in combination with a second therapeutic agent or modality to treat pancreatic cancer. In some embodiments, the second therapeutic agent or modality comprises a chemotherapeutic agent (eg, gemcitabine).

In certain embodiments, the cancer is melanoma. In some embodiments, the melanoma is HLA-A2 positive, stage II, III, or IV melanoma, unresectable melanoma, or metastatic melanoma. In some embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is administered as a single agent to treat melanoma. In other embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is administered in combination with a second therapeutic agent or modality to treat melanoma. In some embodiments, the second therapeutic agent or modality is an HLA-A2 peptide. In certain embodiments, the anti-LAG-3 antibody molecule, or a composition or agent comprising the anti-LAG-3 antibody molecule, and, optionally, the HLA-A2 peptide is administered to a patient without disease melanoma. In some embodiments, the second therapeutic agent or modality comprises a PD-1 inhibitor or PD-L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, eg, an anti-PD-1 antibody described herein. In certain embodiments, the anti-PD-1 antibody molecule is PDR001. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, eg, an anti-PD-L1 antibody molecule described herein.

In certain embodiments, the cancer is renal cancer. In some embodiments, the renal cancer is renal cell carcinoma (RCC), such as metastatic renal cell carcinoma. In some embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is administered as a single agent to treat renal cancer. In other embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is a second therapeutic agent or modality for treating renal cancer, such as a PD-1 inhibitor or PD- It is administered in combination with an L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, eg, an anti-PD-1 antibody described herein. In certain embodiments, the anti-PD-1 antibody molecule is PDR001. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, eg, an anti-PD-L1 antibody molecule described herein.

In certain embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is metastatic breast carcinoma. In some embodiments, the breast cancer is triple negative breast cancer (TNBC). In some embodiments, the anti-LAG-3 antibody molecule, or composition or agent comprising the anti-LAG-3 antibody molecule, is administered as a single agent to treat breast cancer. In other embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is administered in combination with a second therapeutic agent or modality to treat breast cancer. In certain embodiments, the second therapeutic agent or modality is a chemotherapeutic agent (eg, paclitaxel). In certain embodiments, the anti-LAG-3 antibody molecule is administered once every 4 weeks at a dose of about 700 mg to about 900 mg to treat breast cancer (eg, TNBC).

In certain embodiments, the cancer is a virus-associated tumor. In some embodiments, the virus-associated tumor is anal canal cancer (eg, squamous cell carcinoma of the anal canal), cervical cancer (eg, squamous cell carcinoma of the cervix), gastric cancer (eg, Epstein Barr virus (EBV) ) Benign gastric cancer or gastric or gastro-esophageal carcinoma), head and neck cancer (e.g. HPV positive and negative squamous cell head and neck cancer (SCCHN)), nasopharyngeal cancer (NPC), penile cancer (e.g. squamous cells of the penis) Carcinoma), vaginal or vulvar cancer (eg, squamous cell carcinoma of the vagina or vulva). In some embodiments, the anti-LAG-3 antibody molecule, or composition or agent comprising the anti-LAG-3 antibody molecule, is administered as a single agent to treat a virus-associated tumor. In other embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is a second therapeutic agent or modality for treating a virus-associated tumor, such as a PD-1 inhibitor Or in combination with a PD-L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, eg, an anti-PD-1 antibody described herein. In certain embodiments, the anti-PD-1 antibody molecule is PDR001. In other embodiments, the anti-PD-1 antibody molecule is nivolumab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, eg, an anti-PD-L1 antibody molecule described herein.

In certain embodiments, the cancer is anal canal cancer (e.g., squamous cell carcinoma of the anal canal), cervical cancer (e.g., squamous cell carcinoma of the cervix), gastric cancer (e.g., Epstein Barr virus (EBV) positive gastric cancer) Or gastric or gastro-esophageal junction carcinoma), head and neck cancer (eg HPV positive and negative squamous cell head and neck cancer (SCCHN)), nasopharyngeal cancer (NPC), penile cancer (eg, squamous cell carcinoma of the penis), Or vaginal or vulvar cancer (eg, squamous cell carcinoma of the vagina or vulva). In some embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is administered as a single agent to treat cancer. In other embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is a second therapeutic agent or modality for treating cancer, eg, a PD-1 inhibitor or PD- It is administered in combination with an L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, eg, an anti-PD-1 antibody described herein. In certain embodiments, the anti-PD-1 antibody molecule is PDR001. In other embodiments, the anti-PD-1 antibody molecule is nivolumab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, eg, an anti-PD-L1 antibody molecule described herein.

In certain embodiments, the cancer is colorectal cancer. In some embodiments, the colorectal cancer is recurrent colorectal cancer, metastatic colorectal cancer, microsatellite unstable colorectal cancer, microsatellite stable colorectal cancer, mismatch recovery proficient colorectal cancer, or colorectal cancer lacking mismatch recovery. In some embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is administered as a single agent to treat colorectal cancer. In other embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is a second therapeutic agent or modality for treating colorectal cancer, such as a PD-1 inhibitor or PD -L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, eg, an anti-PD-1 antibody described herein. In certain embodiments, the anti-PD-1 antibody molecule is PDR001. In other embodiments, the anti-PD-1 antibody molecule is nivolumab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, eg, an anti-PD-L1 antibody molecule described herein.

In certain embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is administered as a single agent to treat lung cancer. In other embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is a second therapeutic agent or modality for treating lung cancer, such as a PD-1 inhibitor or PD- It is administered in combination with an L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, eg, an anti-PD-1 antibody described herein. In certain embodiments, the anti-PD-1 antibody molecule is PDR001. In other embodiments, the anti-PD-1 antibody molecule is nivolumab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, eg, an anti-PD-L1 antibody molecule described herein.

In certain embodiments, the cancer is blood cancer. In some embodiments, the blood cancer is a lymphoma, eg, Hodgkin's lymphoma (HL) or diffuse versus B cell lymphoma (DCBCL) (eg, recurrent or refractory HL or DCBCL). In some embodiments, the anti-LAG-3 antibody molecule, or composition or formulation comprising the anti-LAG-3 antibody molecule, is administered as a single agent to treat blood cancer. In other embodiments, the anti-LAG-3 antibody molecule, or composition or agent comprising the anti-LAG-3 antibody molecule, is administered in combination with a second therapeutic agent or modality to treat blood cancer.

The methods and compositions disclosed herein are useful for treating metastatic lesions associated with the aforementioned cancers.

In some embodiments, the method determines whether the tumor sample is positive for one or more of PD-L1, CD8, and IFN-γ, and the tumor sample is one or more of the markers, for example two, or all If positive for the three, further comprising administering to the patient a therapeutically effective amount of an anti-LAG-3 antibody molecule in combination with one or more other immunomodulatory agents or anti-cancer agents as described herein.

In some embodiments, anti-LAG-3 antibody molecules are used to treat cancer expressing LAG-3. LAG-3-expressing cancers include, for example, colorectal cancer (Xiao and Freeman Cancer Discov. 2015; 5 (1): 16-8), breast cancer (Bottai et al. Breast Cancer Res. 2016; 18 (1): 121), prostate cancer (Sfanos et al. Clin Cancer Res. 2008; 14 (11): 3254-61), lung cancer (He et al. J Thorac Oncol. 2017; 12 (5): 814-823), and liver cancer (Pedroza-Gonzalez et al. Oncoimmunology. 2015; 4 (6): e1008355). LAG-3-expressing cancer may be metastatic cancer.

In other embodiments, the anti-LAG-3 antibody molecule is used to treat cancer characterized by high-microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR). Identification of MSI-H or dMMR tumor status in a patient can be determined, for example, using polymerase chain reaction (PCR) testing in the case of MSI-H status or immunohistochemistry (IHC) testing in the case of dMMR. Methods for determining MSI-H or dMMR tumor status are described, for example, in Ryan et al. Crit Rev Oncol Hematol. 2017; 116: 38-57; Dietmaier and Hofstadter. Lab Invest 2001, 81: 1453-1456; Kawakami et al. Curr Treat Options Oncol. 2015; 16 (7): 30).

Combination therapies described herein are co-formulated and / or co-formulated with one or more additional therapeutic agents, e.g., one or more anti-cancer agents, cytotoxic agents or cytostatic agents, hormone therapy, vaccines, and / or other immunotherapy. It may include a composition of the present invention to be administered. In other embodiments, the antibody molecule is administered in combination with other therapeutic modalities, including surgery, radiation, cryosurgery, and / or thermotherapy. Such combination therapy can advantageously avoid possible toxicity or complications associated with various monotherapy by using lower doses of the administered therapeutic agent.

The methods, compositions and combinations described herein (e.g., anti-LAG-3 antibodies and methods using them) are described in WO 2017/019897, which is incorporated by reference in its entirety in other agents or treatment modalities, e.g. It can be used in combination with a second therapeutic agent selected from one or more of the agents listed in Table 6. In one embodiment, a method described herein provides an subject with an anti-LAG-3 antibody molecule (optionally PD-1, PD-L1, TIM-3, CEACAM (e.g., CEACAM-1) as described in WO2017 / 019894. And / or CEACAM-5), or in combination with an inhibitor of one or more of CTLA-4), such as administering in an amount effective to treat or prevent the disorder, eg, a disorder as described herein, such as cancer. , Further comprising administering a second therapeutic agent selected from one or more of the agents listed in Table 6 of WO 2017/019897. When administered in combination, the anti-LAG-3 antibody molecule, additional agent (e.g., second or third agent), or both, is the amount of each agent individually used, e.g., as monotherapy Or higher, lower, or the same amount or dose as the dose. In certain embodiments, the administered amount or dosage of the anti-LAG-3 antibody molecule, additional agent (e.g., second or third agent), or both, is used separately, for example as monotherapy Lower than the amount or dose of each agent (eg, at least 20%, at least 30%, at least 40%, or at least 50%). In other embodiments, the amount or administration of an anti-LAG-3 antibody molecule, an additional agent (e.g., a second or third agent), or both, that produces the desired effect (e.g., treatment of cancer) The amount is lower (eg, at least 20%, at least 30%, at least 40%, or at least 50% lower).

In other embodiments, the additional therapeutic agent is selected from one or more of the agents listed in Table 6 of WO 2017/019894. In some embodiments, the additional therapeutic agent is selected from one or more of the following, eg, as described in Table 6 of WO 2017/019894: 1) protein kinase C (PKC) inhibitors; 2) Heat shock protein 90 (HSP90) inhibitors; 3) inhibitors of phosphoinositide 3-kinase (PI3K) and / or the target of rapamycin (mTOR); 4) inhibitors of cytochrome P450 (eg, CYP17 inhibitor or 17 alpha-hydroxylase / C17-20 lyase inhibitor); 5) iron chelating agents; 6) aromatase inhibitors; 7) Inhibitors of p53, eg, inhibitors of the p53 / Mdm2 interaction; 8) apoptosis inducers; 9) angiogenesis inhibitors; 10) aldosterone synthase inhibitors; 11) Smooth (SMO) receptor inhibitors; 12) prolactin receptor (PRLR) inhibitors; 13) Wnt signaling inhibitors; 14) CDK4 / 6 inhibitors; 15) Fibroblast Growth Factor Receptor 2 (FGFR2) / Fibroblast Growth Factor Receptor 4 (FGFR4) inhibitors; 16) Inhibitors of macrophage colony-stimulating factor (M-CSF); 17) c-KIT, histamine release, Flt3 (eg, FLK2 / STK1) or one or more inhibitors of PKC; 18) one or more inhibitors of VEGFR-2 (eg, FLK-1 / KDR), PDGFRbeta, c-KIT or Raf kinase C; 19) Somatostatin agonists and / or growth hormone release inhibitors; 20) an anaplastic lymphoma kinase (ALK) inhibitor; 21) Insulin-like growth factor 1 receptor (IGF-1R) inhibitors; 22) P-glycoprotein 1 inhibitor; 23) vascular endothelial growth factor receptor (VEGFR) inhibitors; 24) BCR-ABL kinase inhibitors; 25) FGFR inhibitors; 26) inhibitors of CYP11B2; 27) HDM2 inhibitors, eg, inhibitors of the HDM2-p53 interaction; 28) inhibitors of tyrosine kinase; 29) inhibitors of c-MET; 30) inhibitors of JAK; 31) inhibitors of DAC; 32) inhibitors of 11β-hydroxylase; 33) inhibitors of IAP; 34) inhibitors of PIM kinase; 35) inhibitors of porcupine; 36) BRAF, eg BRAF V600E or an inhibitor of wild type BRAF; 37) inhibitors of HER3; 38) inhibitors of MEK; Or 39) an inhibitor of lipid kinase.

Additional embodiments of combination therapies comprising anti-LAG-3 antibody molecules described herein are described in WO 2017/019894, which is incorporated by reference in its entirety.

How to treat infectious diseases

Anti-LAG-3 antibody molecule (e.g., anti-LAG-3 antibody molecule described herein), or composition or agent comprising an anti-LAG-3 antibody molecule (e.g., composition or agent described herein) Methods of treating infectious diseases using are disclosed herein. In certain embodiments, the antibody molecule, composition, or formulation is administered to a subject according to the dosing regimen described herein.

In certain embodiments, the anti-LAG-3 antibody molecule is administered in an amount effective to treat an infectious disease or symptom thereof. In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 100 mg to about 2000 mg once every 2 weeks, once every 3 weeks, or once every 4 weeks. For example, the anti-LAG-3 antibody molecule may be from about 200 mg to about 1000 mg, from about 300 mg to about 900 mg, from about 200 mg to about 600 mg, from about 300 mg to about 500 mg, from about 600 to about 1000 mg , About 700 mg to about 900 mg, or about 400 mg to about 800 mg, may be administered once every 3 weeks or once every 4 weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to 500 mg (eg, about 400 mg). In one embodiment, the anti-LAG-3 antibody molecule is administered once every 4 weeks at a dose of about 700 mg to about 900 mg (eg, about 800 mg). In one embodiment, the anti-LAG-3 antibody molecule is administered once every 4 weeks at a dose of about 500 mg to about 700 mg (eg, about 533 mg or about 600 mg).

Certain methods described herein are used to treat subjects exposed to specific toxins or pathogens. Without wishing to be bound by theory, in some embodiments, the anti-LAG-3 antibody is capable of stimulating NK cell mediated killing of target cells and enhancing IFN-gamma secretion and proliferation of CD4 + T cells. Is considered. Thus, in certain embodiments, the anti-LAG-3 antibody molecules, compositions, and formulations described herein are suitable for use in stimulating an immune response to an infectious agent. Accordingly, another aspect of the invention provides the subject with administration of an anti-LAG-3 antibody molecule, or a composition or formulation comprising an anti-LAG-3 antibody molecule, for example, according to a dosing regimen described herein. Provided are methods of treating an infectious disease in a subject, including allowing treatment for the infectious disease. In the treatment of infections (eg, acute and / or chronic), administration of anti-LAG-3 antibody molecules can be combined with conventional treatments in addition to or instead of stimulating natural host immune defenses against infections. have. Natural host immune defenses against infection include inflammation, fever, antibody-mediated host defense, T-lymphocyte-mediated host defense, such as lymphokine secretion and cytotoxic T-cells (especially during viral infection), complement mediated lysis and opsonin Anger (which facilitates phagocytosis), and phagocytosis. The ability of the anti-LAG-3 antibody molecule to reactivate dysfunctional T-cells will be useful in the treatment of chronic infections, particularly those in which cell-mediated immunity is important for complete recovery.

Similar to its application to tumors as discussed in the previous section, the anti-LAG-3 antibody molecules, compositions, and formulations described herein, alone or as a second therapeutic agent, to stimulate the immune response to pathogens or toxins Or in adjuvant in combination with modality or vaccine. Examples of pathogens for which this therapeutic approach may be particularly useful include pathogens that currently do not have an effective vaccine, or pathogens where conventional vaccines are less completely effective. These include, but are not limited to, HIV, hepatitis (A, B, & C), influenza, herpes, Giardia, malaria, leishmania, Staphylococcus aureus, and Pseudomonas aeruginosa. It is not limited. Anti-LAG-3 antibody molecular therapy is also particularly useful for infections established by agents such as HIV that present altered antigens over the course of the infection.

Thus, in some embodiments, the anti-LAG-3 antibody molecule, composition, or formulation described herein is used to treat a subject who has or is at risk of having an infection. Infection, for example, refers to a disease or condition resulting from the presence of a foreign organism or agent that is reproduced in the host in the host. Infection typically involves the destruction of normal mucosal or other tissue barriers by an infectious organism or source of infection. A subject with an infection is a subject with an objectively measurable infectious organism or source of infection present in the subject's body. Subjects at risk of having an infection are subjects who are predisposed to develop the infection. Such subjects can include, for example, subjects with known or suspected exposure to an infectious organism or source of infection. Subjects at risk of infection may also be those with conditions associated with impaired ability to mount an immune response to an infectious organism or agent, such as subjects with congenital or acquired immunodeficiencies, subjects undergoing radiation therapy or chemotherapy, Subjects with burn injury, subjects with traumatic damage, subjects undergoing surgery or other invasive medical or dental procedures.

Infections are broadly classified as bacterial, viral, fungal or parasitic infections based on the category of contagious infectious organism or source of infection. Other less common types of infection include, for example, Rickettsia concomitant infections, Mycoplasma concomitant infections, and infectious agents that cause scrapie, bovine spongiform encephalopathy (BSE) and prion diseases (e.g., Kuru's disease and Creutzfeldt-Jakob disease). Infections. Examples of bacteria, viruses, fungi and parasites causing infection are well known in the art. The infection can be acute, subacute, chronic or latent, and can be local or systemic. In addition, the infection can be predominantly intracellular or extracellular during at least one phase of the life cycle of the infectious organism or infectious agent in the host.

virus

In certain embodiments, anti-LAG-3 antibody molecules, compositions, or agents described herein are used to treat viral infections or diseases associated with viruses.

Examples of viruses that have been found to cause infection in humans are Retroviridae (eg, human immunodeficiency virus, such as HIV-1 (also referred to as HTLV-III), HIV-2, LAV or HTLV-III / LAV, or HIV-III, and other isolates, such as HIV-LP; Picornaviridae (eg, poliovirus, hepatitis A virus; enterovirus, human coxsackie virus, Reno Virus, ecovirus); Caliciviridae (e.g., strains that cause gastroenteritis); Togaviridae (e.g. equine encephalitis virus, rubella virus); flaviviridae ( Flaviviridae) (e.g. dengue virus, encephalitis virus, yellow fever virus); Coronaviridae (e.g. coronavirus); Rhabdoviridae (e.g. blep stomatitis virus, rabies Virus); Phil Filoviridae (e.g., Ebola virus); Paramyxoviridae (e.g., parainfluenza virus, mumps virus, measles virus, respiratory syncytial virus); orthomyxoviridae ( Orthomyxoviridae) (e.g., influenza virus); Bunyaviridae (e.g., Hantan virus, Bunga virus, Flevovirus and Nairo virus); Arena viridae (Hemorrhagic fever virus); Leo Reoviridae (e.g., Leovirus, Orbivirus and Rotavirus); Birnaviridae; Hepadnaviridae (Hepatitis B virus); Parvoviridae (Parvoviridae) ( Parvovirus); Papovaviridae (papilloma virus, polyoma virus); Adenoviridae (most adenovirus); Herpesviridae (herpes simplex virus (HSV) 1 and 2, varicella zoster virus, cytomegalovirus (CMV), herpes virus; Poxviridae (pox virus, vaccinia virus, fox virus); And Iridoviridae (e.g., African swine fever virus); and unclassified virus (e.g., causative agent of spongiform encephalopathy, pathogen of delta hepatitis (presumed to be a defective satellite of the hepatitis B virus)) , Etiology of non-A, non-hepatitis B (Class 1 = propagated to the intestine; Class 2 = propagated to the parenteral (ie, hepatitis C); Norwalk and related viruses and astroviruses). Some examples of pathogenic viruses that cause infections treatable by HIV, hepatitis (type A, B or C), herpes viruses (e.g. VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Bar virus), adenovirus Swine, influenza virus, flavivirus, ecovirus, rhinovirus, coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, Dengue virus, papilloma virus, serial virus, polio virus, rabies virus, JC virus and arbovirus encephalitis virus.

For infections arising from viral causes, anti-LAG-3 antibody molecules can be combined by application of standard therapies to treat viral infections, concurrently, before or after application. This standard therapy depends on the type of virus, but in almost all cases administration of human serum containing antibodies specific to the virus (eg, IgA, IgG) may be effective.

Some examples of pathogenic viruses that cause infections treatable by the method include HIV, hepatitis (type A, B or C), herpes viruses (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flavivirus, ecovirus, rhinovirus, coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus , Vaccinia virus, HTLV virus, dengue virus, papilloma virus, serial virus, poliovirus, rabies virus, JC virus, arbovirus encephalitis virus and Ebola virus (eg BDBV, EBOV, RESTV, SUDV and TAFV) Includes.

In one embodiment, the infection is an influenza infection. Influenza infection can cause fever, cough, muscle aches, headaches and boredom, and often occurs in a seasonal epidemic. Influenza is also associated with a number of post-infection disorders, such as encephalitis, myocardial pericarditis, Goodpasture's syndrome, and Reie's syndrome. Influenza infection also inhibits normal pulmonary antibacterial defense, increasing the risk of developing bacterial pneumonia when patients recover from influenza. Influenza virus surface proteins exhibit distinct antigenic variations, due to mutations and recombination. Thus, cytolytic T lymphocytes are the host's primary vehicle for the removal of viruses after infection. Influenza is classified into three main types: A, B and C. Influenza A infects both humans and many other animals (e.g. pigs, horses, birds and seals) and is the main cause of pandemic influenza. It is peculiar in In addition, when cells are infected with two different influenza A strains, the fragmented RNA genomes of the two parental virus types are mixed during replication to produce a hybrid replica, which results in a new epidemic strain. Influenza B does not replicate in animals and therefore has less genetic variation, and influenza C has only a single serotype.

The most common therapy is an alleviator of symptoms caused by infection, while the host's immune response substantially clears the disease. However, certain strains (eg influenza A) can cause more serious illness and death. Influenza A can be treated both clinically and prophylactically by administering the cyclic amine inhibitors adamantine and rimantadine, which inhibit viral replication. However, the clinical utility of these drugs is limited due to the relatively high incidence of adverse reactions, their narrow antiviral spectrum (influenza A alone), and the tendency of the virus to make resistance. Administration of serum IgG antibodies to major influenza surface proteins, hemagglutinin and neuraminidase can prevent lung infection, while mucosal IgA is required to prevent infection of the upper respiratory tract and organs. The most effective current treatment for influenza is vaccination by administration of virus inactivated with formalin or β-proriolactone.

In another embodiment, the infection is a hepatitis infection, such as a hepatitis B or C infection.

Hepatitis B virus (HB-V) is the most infectious known hematogenous pathogen. It is a major cause of acute and chronic hepatitis and liver carcinoma, as well as lifelong chronic infection. After infection, the virus replicates in the hepatocytes, which in turn releases the surface antigen HBsAg. Detecting excessive levels of HBsAg in serum is used as a standard method for diagnosing hepatitis B infection. Acute infections can be resolved, or they can develop into chronic persistent infections. Current chronic HBV treatments include α-interferon, which increases the expression of class I human leukocyte antigen (HLA) on the surface of hepatocytes, thereby facilitating its recognition by cytotoxic T lymphocytes. Additionally, nucleoside analogues Gancyclovir, Palmcyclovir and Lamivudine also showed some efficacy in treating HBV infection in clinical trials. Additional treatments of HBV include PEGylated a-interferon, adefovir, entecavir and telbivudine. While passive immunity can be conferred through parental administration of anti-HBsAg serum antibodies, inactivation or vaccination with recombinant HBsAg also confers resistance to infection. Anti-LAG-3 antibody molecules can be combined with conventional treatment for hepatitis B infection for therapeutic benefit.

Hepatitis C virus (HC-V) infection can lead to chronic form of hepatitis and cause cirrhosis. Symptoms are similar to infections due to hepatitis B, but in stark contrast to HB-V, infected hosts can be asymptomatic for 10-20 years. The anti-LAG-3 antibody molecule can be administered as monotherapy or combined with standard care for hepatitis C infection. For example, the anti-LAG-3 antibody molecule can be administered with one or more of Sovaldi (Sophosbuvir), Olysio (Cimeprevir), in addition to ribavirin or PEGylated interferon. . Therapies that include Incivek (Telaprevir) or Victrelis (Boseprevir) in addition to ribavirin or PEGylated interferon are also approved, but they have increased side effects and longer treatment duration and Associated and therefore not considered a preferred therapy.

Conventional treatment for HC-V infection involves the administration of a combination of α-interferon and ribavirin. A promising potential therapy for HC-V infection is the protease inhibitor telaprevir (VX-960). Additional treatments include: anti-PD-1 antibody (MDX-1106, Medarex), babuximab (an antibody that binds to anionic phospholipid phosphatidylserine in a B2-glycoprotein I dependent manner, peregrin famashti Peregrine Pharmaceuticals), anti-HPV virus coat protein E2 antibody (s) (e.g., ATL 6865-Ab68 + Ab65, XTL Pharmaceuticals) and Civacir® (polyclonal) Anti-HCV human immunoglobulin). The anti-LAG-3 antibodies of the invention can be combined with one or more of these treatments for hepatitis C infection for therapeutic benefit. In particular proteases, polymerases and NS5A inhibitors that can be used in combination with anti-LAG-3 antibody molecules to treat hepatitis C infection include those described in US 2013/0045202, incorporated herein by reference.

In another embodiment, the infection is measles virus. After 9-11 days of incubation, the host infected with the measles virus develops fever, cough, nasal cold and conjunctivitis. Within 1-2 days, erythematous, spotty rashes develop, which spread rapidly throughout the body. Because infection also inhibits cellular immunity, the host is at greater risk of developing bacterial overlapping infections, including otitis media, pneumonia, and post-infection encephalomyelitis. Acute infections are associated with marked morbidity and mortality, especially in malnourished adolescents.

Treatment for measles involves passive administration of pooled human IgG, which can prevent infection in non-immunized subjects even up to one week after exposure. However, pre-immunization with a live attenuated virus is the most effective treatment, and disease is prevented in more than 95% of immunization cases. Since there is one serotype of this virus, a single immunization or infection typically protects against subsequent infections throughout life.

In a small population of infected hosts, measles can develop into SSPE, a chronic progressive nervous system disorder caused by persistent infection of the central nervous system. SSPE is caused by clonal variants of the measles virus with defects that interfere with virion assembly and budding. For these patients, reactivation of T-cells with anti-LAG-3 antibody molecules that facilitate viral clearance would be desirable.

In another embodiment, the infection is HIV. HIV attacks CD4 ⁺ cells, including T-lymphocytes, monocyte-macrophages, follicular dendritic cells, and Langerhans cells, and CD4 ⁺ helper / inducer cells are depleted. As a result, the host acquires severe defects in cell-mediated immunity. Infection with HIV causes AIDS in at least 50% of individuals, and sexual contact, administration of infected blood or blood products, artificial insemination with infected semen, exposure to blood-containing needles or syringes, and infants from infected mothers during childbirth It is spread through the propagation of furnace.

Hosts infected with HIV can be asymptomatic or develop into acute diseases similar to mononucleosis-fever, headache, sore throat, boredom and rash. Symptoms can progress to progressive immune dysfunction, including persistent fever, night sweating, weight loss, diarrhea difficult to explain, eczema, psoriasis, seborrheic dermatitis, shingles, oral candidiasis, and oral vitiligo. Opportunistic infections by host parasites are common in patients whose infections have developed into AIDS.

Treatment for HIV includes antiviral therapy including nucleoside analogs, zidovudine (AST), dideoxyinosine, dideoxycytidine, lamidvudine, stavudine, alone or in combination with didanosine or zalcitabine; Reverse transcriptase inhibitors, such as delavirdine, nevirapine, roviride, and proteinase inhibitors, such as saquinavir, ritonavir, indinavir, and nelfinavir. Anti-LAG-3 antibody molecules can be combined with conventional treatment for HIV infection for therapeutic benefit.

In another embodiment, the infection is cytomegalovirus (CMV). CMV infections are often associated with persistent, latent and recurrent infections. CMV infects monocytes and granulocyte-monocyte progenitor cells and has potential in them. Clinical symptoms of CMV include mononucleosis-like symptoms (ie fever, hypertrophy of the gland, malaise) and a tendency to develop an allergic skin rash against antibiotics. Viruses are spread by direct contact. Viruses are present in urine, saliva, semen and other body fluids to a lesser extent. Propagation can also occur from an infected mother to her fetus or newborn, and can be by blood transfusion and organ transplantation. CMV infection causes general cellular immune damage, characterized by impaired blastogenic responses to non-specific mitogens and specific CMV antigens, reduced cytotoxicity and elevated CD4 + lymphocyte CD8 lymphocyte count.

Treatment of CMV infections includes antiviral ganciclovir, phoscarnet and cidovir, but these drugs are typically prescribed only in immunocompromised patients. Anti-LAG-3 antibody molecules can be combined with conventional treatment for cytomegalovirus infections for therapeutic benefit.

In another embodiment, the infection is Epstein-Barr virus (EBV). EBV can establish persistent and latent infections, primarily attacking B cells. Infection with EBV causes a clinical state of infectious mononucleosis, which includes fever, sore throat (often containing secretions), systemic lymphadenopathy, and nontrophic hypertrophy. Hepatitis may also be present, which can develop into jaundice.

A typical treatment for EBV infection is relief of symptoms, and EBV is associated with the development of certain cancers, such as Burkitt's lymphoma and nasopharyngeal cancer. Therefore, clearance of viral infections before inducing these complications would be very beneficial. Anti-LAG-3 antibody molecules can be combined with conventional treatment for Epstein-Barr virus infection for therapeutic benefit.

In another embodiment, the infection is herpes simplex virus (HSV). HSV is spread by direct contact with an infected host. Direct infection can be asymptomatic, but typically causes blisters containing infectious particles. The disease manifests as a cycle of the active phase of the disease, where the lesion potentially develops and disappears as the virus potentially infects the ganglion and subsequently develops. Lesions can occur on the face, genitals, eyes and / or hands. In some cases, infection can also cause encephalitis.

Treatment for herpes infection is primarily directed to addressing the onset of symptoms, systemic antiviral medications such as acyclovir (e.g. Zovirax®), valacyclovir, palmcyclovir, phencyclovir and Topical medicines, such as docosanol (Abreva®), tromantadine, and zylactin. Clearance of herpes latent infections will have great clinical benefit. Anti-LAG-3 antibody molecules can be combined with conventional treatment for herpes virus infection for therapeutic benefit.

In another embodiment, the infection is human T-lymphogenic virus (HTLV-1, HTLV-2). HTLV is transmitted through sexual contact, breastfeeding, or exposure to contaminated blood. Viruses activate a subset of TH cells called Th1 cells, causing overproduction and overproduction of Th1-related cytokines (eg, IFN-γ and TNF-α). This results in inhibition of Th2 lymphocytes and reduction of Th2 cytokine production (e.g., IL-4, IL-5, IL-10 and IL-13), requiring an infected host to have a Th2-dependent response for clearance. It reduces the ability to mount an appropriate immune response against the invading organism (eg, parasitic infection, production of mucosal and humoral antibodies).

HTLV infection causes opportunistic infections, leading to bronchiectasis, dermatitis and overlapping infections by Staphylococcus spp. And Strongyloides spp., Leading to death due to multiplicity of sepsis. HTLV infection can also lead directly to adult T-cell leukemia / lymphoma and progressive demyelinating upper motor neuron disease known as HAM / TSP. Clearance of HTLV latent infections will have great clinical benefit. Anti-LAG-3 antibody molecules can be combined with conventional treatment for HTLV infection for therapeutic benefit.

In another embodiment, the infection is human papilloma virus (HPV). HPV primarily affects keratinocytes, and occurs in two forms: in the skin and genitals. Propagation is believed to occur through direct contact and / or sexual activity. Both skin and genital HPV infections can cause warts and latent infections and sometimes recurrent infections, which are controlled by host immunity that controls symptoms and blocks the appearance of warts, but the host can spread the infection to others. The ability to remain.

Infection with HPV can also lead to certain cancers, such as cervical cancer, anal cancer, vulvar cancer, penile cancer and oropharyngeal cancer. There is no known cure for HPV infection, but the current treatment is topical application of imiquimod, which stimulates the immune system to attack the affected area. Clearance of HPV latent infection will have great clinical benefit. The anti-LAG-3 antibodies of the present invention can be combined with conventional HPV infection treatment for therapeutic benefit.

In another embodiment, the infection is Ebola virus (EBOV). EBOV is one of five known viruses in the genus Ebola. EBOV causes severe and often fatal hemorrhagic fever in humans and mammals, known as Ebola Virus Disease (EVD). Propagation occurs through contact with an infected patient's blood, secretions, organs, or other body fluids. Currently, there is no proven treatment or vaccine.

bacteria

In certain embodiments, anti-LAG-3 antibody molecules, compositions, or agents described herein are used to treat bacterial infections or diseases associated with bacteria.

Bacteria include both Gram negative and Gram positive bacteria. Examples of Gram-positive bacteria include, but are not limited to, Pasteurella species, Staphylococci species, and Streptococcus species. Examples of Gram-negative bacteria include, but are not limited to, Escherichia coli, Pseudomonas species, and Salmonella species. Specific examples of infectious bacteria are Helicobacter pyloris, Borrelia burgdorferi, Legionella pneumophilia, Mycobacteria species (e.g. M. tuberculosis ( M. tuberculosis, M. avium, M. intracellulare, M. kansasii, M. gordonae, Staphylo Staphylococcus aureus, Neisseria gonorrhoeae, Neisseria meningitidis, Listeria monocytogenes, Streptococcus pyogenes (Group A Streptococcus), Streptococcus agalactiae (Group B Streptococcus), Streptococcus (viridans group), Streptococcus faecalis, Streptococcus faecalis Streptococcus bovis, Streptococcus (anaerobic species), Streptococcus pneumoniae, Pathogenic Campylobacter species, Enterococcus species, Haemophilus influenzae influenzae), Bacillus anthracis, Corynebacterium diphtheriae, Corynebacterium species, Erysipelothrix rhusiopathiae, Clostridium perstridium ), Clostridium tetani, Enterobacter aerogenes, Klebsiella pneumoniae, Pasteurella multocida, Bacteroides ) Species, Fusobacterium nucleatum, Streptobacillus moniliformis, Trefo Treponema pallidum, Treponema pertenue, Leptospira, Mycobacterium leprae, Rickettsia, and Actinomyces israelii It includes, but is not limited to. Some examples of pathogenic bacteria that cause infections treatable by the methods herein are chlamydia, rickettsiae bacteria, mycobacteria, staphylococcus, streptococcus, pneumococcus, meningococcus, and gonococcus, clevciella , Proteus, Ceratia, Pseudomonas, Legionella, Diphtheria, Salmonella, Bacillus, Cholera, Tetanus, Botulinum Toxin, Anthrax, Black Death, Leptospirosis and Lyme Disease bacteria.

Some examples of pathogenic bacteria that cause infections treatable by the methods of the present invention are syphilis, chlamydia, rickettsiae bacteria, mycobacteria, staphylococcus, streptococcus, pneumococcus, meningococcus and conococcus, clevis Bsiella, Proteus, Ceratia, Pseudomonas, Legionella, Diphtheria, Salmonella, Bacillus, Cholera, Tetanus, Botulinum Toxin, Anthrax, Black Death, Leptospirosis and Lyme Disease bacteria. Anti-LAG-3 antibody molecules can be used in combination with existing treatment modalities for the infection. For example, treatments for syphilis include penicillin (eg, penicillin g.), Tetracycline, doxycycline, cetriaxone and azithromycin.

Lyme disease caused by Borrelia burgdorferi is transmitted to humans through tick bites. The disease initially manifests as a local rash and then exhibits flu-like symptoms including boredom, fever, headache, neck stiffness and joint pain. Subsequent findings may include juvenile and polyarthritis, nervous system and cardiac involvement, myocarditis and arrhythmia with cerebral nerve palsy and neuromyopathy. Some cases of Lyme disease persist, causing irreversible damage similar to tertiary syphilis. Current therapies for Lyme disease mainly involve the administration of antibiotics. Antibiotic-resistant strains can be treated with hydroxychloroquine or methotrexate. Antibiotic refractory patients with neuropathic pain can be treated with gabapentin. Minocycline may help with late / chronic Lyme disease with nervous system or other inflammatory signs.

Other forms of borreliosis, such as rain. B. recurentis, B. B. hermsii, B. B. turicatae, b. B. parikeri., B. B. hispanica, b, dutonnii and b. Leptospirosis (eg, L. interrogans), as well as those originating from B. persica, typically resolve spontaneously unless blood titers reach concentrations that cause intrahepatic disorders. .

Fungi and parasites

In certain embodiments, the anti-LAG-3 antibody molecules, compositions, or agents described herein are used to treat fungal or parasitic infections or diseases associated with fungal or parasites.

Examples of fungi are Aspergillus species, Blastomyces dermatitidis, Candida albicans, other Candida species, Coccidioides immitis, Cryptococcus Includes Neoptmans (Cryptococcus neoformans), Histoplasma capsulatum, Chlamydia trachomatis, Nocardia spp, Pneumocystis carinii. Some examples of pathogenic fungi that cause infections treatable by the methods herein are Candida (Albicans, Crussie, Glabrata, Tropicalis, etc.), Cryptococcus neoformans, Aspergillus (Fumigatus) , Niger et al.), Genus Mucorales (Mucor, Absidia, Rizopus), Sporothrix schenckii, Blastomyces dermatitidis, Paracoccidioides bra And Parasiccisis (Paracoccidioides brasiliensis), Coccidioides immitis and Histoplasma capsulatum.

Parasites are blood system and / or tissue parasites such as Babesia microti, Babesia divergens, Entamoeba histolytica, Giardia lamblia, Leish Leishmania tropica, Leishmania species, Leishmania braziliensis, Leishmania donovani, Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, Plasmodium vivax, and Toxoplasma gondii, Trypanosoma gambiense, and Trypanosoma rhodesiense disease (African cotton) , Trypanosoma cruzi (Chargas disease) and Toxoplasma gondii, flatworms, roundworms. It is not. Some examples of pathogenic parasites that cause infections treatable by the methods herein are Ent Amoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba species, Giar Dia lamblia, Cryptosporidium species, Pneumocystis carini, Plasmodium bibox, Vavesia microti, Trypanosoma brucei, Trypanosoma brucei, Trypanosoma brucei, Tripanosoma crusage, Lismania donovani, Toxoplasma gondii and nipost Longipus brasiliensis.

Some examples of pathogenic fungi that cause infections treatable by the methods of the present invention are Candida (Albicans, Crucesi, Glabrata, Tropicalis, etc.), Cryptococcus neoformans, Aspergillus (Fumiga Tooth, Niger, etc.), of the genus Mucorales (Mucor, Absidia, Rizopus), Sporotrix Genkki, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides imimitis and Histoplasma capsules.

Some examples of pathogenic parasites that cause infections treatable by the methods described herein include Ent Amoeba histolytica, Valentium coli, Neglieria poulelli, Acanthamoeba species, Giardia lamblia, Cryptosporidium species, New Mostis Carini, Plasmodium Vibox, Babysia Microti, Tripanosoma Bruisei, Tripanosoma Cruise, Lismania Donovani, Toxoplasma Gondi and Nipostrongilus brasiliensis.

Nucleic acid

Anti-LAG-3 antibody molecules described herein can be encoded by the nucleic acids described herein. Nucleic acids can be used to produce the anti-LAG-3 antibody molecules described herein.

In certain embodiments, the nucleic acid comprises a nucleotide sequence encoding heavy and light chain variable regions and CDRs of an anti-LAG-3 antibody molecule as described herein. For example, the present disclosure encodes heavy and light chain variable regions, respectively, of an antibody molecule disclosed herein, e.g., an anti-LAG-3 antibody molecule selected from one or more of the antibodies in Table 1 of US 2015/0259420, respectively. It is characterized by first and second nucleic acids. A nucleic acid is a nucleotide sequence encoding any of the amino acid sequences in the tables herein, or a sequence substantially identical thereto (e.g., a sequence that is at least about 85%, 90%, 95%, 99% or more identical thereto) , Or 3, 6, 15, 30, or 45 or less nucleotides different from the sequence provided in Table 1. For example, BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10, as summarized in Table 1 , BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050 (Ser) (e.g. , BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050- hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19- Ser, or BAP050-hum20-Ser), one or more of BAP050-clone-F, BAP050-clone-G, BAP050-clone-H, BAP050-clone-I, or BAP050-clone-J, for example First and second nucleic acids encoding heavy and light chain variable regions, respectively, of an anti-LAG-3 antibody molecule selected from any one, or substantially the same The sequence is disclosed herein.

In certain embodiments, the nucleic acid is an amino acid sequence as set forth in Table 1, or a sequence substantially homologous thereto (e.g., at least about 85%, 90%, 95%, 99% or more identical thereto) And / or a nucleotide sequence encoding at least 1, 2 or 3 CDRs from a heavy chain variable region having one or more substitutions (eg, sequences with conservative substitutions). In some embodiments, the nucleic acid is an amino acid sequence as set forth in Table 1, or a sequence substantially homologous thereto (e.g., at least about 85%, 90%, 95%, 99% or more identical thereto) And / or a nucleotide sequence encoding at least 1, 2 or 3 CDRs from a light chain variable region having one or more substitutions (eg, sequences with conservative substitutions). In some embodiments, the nucleic acid is an amino acid sequence as set forth in Table 1, or a sequence substantially homologous thereto (e.g., at least about 85%, 90%, 95%, 99% or more identical thereto) And / or a nucleotide sequence encoding at least 1, 2, 3, 4, 5, or 6 CDRs from heavy and light chain variable regions having one or more substitutions, e.g., sequences with conservative substitutions). have.

In certain embodiments, the nucleic acid is a nucleotide sequence as set forth in Table 1, a sequence substantially homologous thereto (e.g., at least about 85%, 90%, 95%, 99% or more identical thereto) / Or a nucleotide sequence encoding at least 1, 2 or 3 CDRs from a heavy chain variable region having a sequence that is hybridizable under the stringent conditions described herein. In some embodiments, the nucleic acid is a nucleotide sequence as set forth in Table 1, or a sequence substantially homologous thereto (e.g., at least about 85%, 90%, 95%, 99% or more identical thereto) And / or a nucleotide sequence encoding at least 1, 2 or 3 CDRs from a light chain variable region having a sequence that is hybridizable under stringent conditions described herein. In certain embodiments, the nucleic acid is a nucleotide sequence as set forth in Table 1, or a sequence substantially homologous thereto (e.g., at least about 85%, 90%, 95%, 99% or more identical thereto) And / or nucleotide sequences encoding at least 1, 2, 3, 4, 5, or 6 CDRs from heavy and light chain variable regions having sequences hybridizable under the stringent conditions described herein. Nucleic acids disclosed herein include deoxyribonucleotides or ribonucleotides, or analogs thereof. The polynucleotide can be single-stranded or double-stranded, and in the case of single-stranded it can be the coding strand or the non-coding (antisense) strand. Polynucleotides can include modified nucleotides, such as methylated nucleotides and nucleotide analogs. Non-nucleotide components may be intervened in the nucleotide sequence. The polynucleotide can be further modified after polymerization, such as by conjugation with a labeling component. The nucleic acid can be a recombinant polynucleotide, or a polynucleotide of genomic, cDNA, semisynthetic or synthetic origin that does not occur in nature or is linked in an unnatural arrangement to another polynucleotide.

In certain embodiments, nucleotide sequences encoding anti-LAG-3 antibody molecules are codon optimized.

In some embodiments, nucleic acids comprising nucleotide sequences encoding heavy and light chain variable regions and CDRs of an anti-LAG-3 antibody molecule as described herein are disclosed. For example, the disclosure provides first and second nucleic acids encoding heavy and light chain variable regions, or sequences substantially identical thereto, of the anti-LAG-3 antibody molecules according to Table 1. For example, a nucleic acid may be a nucleotide sequence encoding an anti-LAG-3 antibody molecule according to Table 1, or a sequence substantially identical to such a nucleotide sequence (e.g., at least about 85%, 90%, 95%, and so on). 99% or more identical sequences, or sequences that differ by up to 3, 6, 15, 30 or 45 nucleotides from the aforementioned nucleotide sequences).

In certain embodiments, the nucleic acid is a nucleotide sequence encoding at least 1, 2, or 3 CDRs or hypervariable loops from a heavy chain variable region having an amino acid sequence as set forth in Table 1, or a sequence substantially homologous thereto ( For example, sequences that are at least about 85%, 90%, 95%, 99% or more identical thereto, and / or 1, 2, 3 or more substitutions, insertions or deletions, such as conservative Sequence with substitutions).

In certain embodiments, the nucleic acid is a nucleotide sequence encoding at least 1, 2, or 3 CDRs or hypervariable loops from a light chain variable region having an amino acid sequence as set forth in Table 1, or a sequence substantially homologous thereto ( For example, sequences that are at least about 85%, 90%, 95%, 99% or more identical thereto, and / or 1, 2, 3 or more substitutions, insertions or deletions, e.g. conservative Sequence with substitutions).

In some embodiments, the nucleic acid is a nucleotide sequence encoding at least 1, 2, 3, 4, 5, or 6 CDRs or hypervariable loops from heavy and light chain variable regions having an amino acid sequence as set forth in Table 1, or Sequences substantially homologous thereto (e.g., sequences that are at least about 85%, 90%, 95%, 99% or more identical thereto, and / or 1, 2, 3 or more substitutions, insertions) Or deletions, eg, sequences with conservative substitutions.

In some embodiments, nucleic acids are isolated or recombinant.

The nucleic acids described herein can be in a single vector or in separate vectors present in the same host cell or in separate host cells, as described in more detail herein.

Vector and host cells

Anti-LAG-3 antibody molecules described herein can be produced using host cells and vectors containing the nucleic acids described herein. Nucleic acids can be in the same host cell or in a single vector or in separate vectors in separate host cells.

In one embodiment, the vector comprises nucleotides encoding the antibody molecules described herein. In one embodiment, the vector comprises nucleotide sequences described herein. Vectors include, but are not limited to, viruses, plasmids, cosmids, lambda phage or yeast artificial chromosomes (YAC).

Numerous vector systems can be used. For example, one class of vectors is an animal virus, such as bovine papilloma virus, polyoma virus, adenovirus, vaccinia virus, baculovirus, retrovirus (Laus sarcoma virus, MMTV or MOMLV) or SV40 virus DNA elements derived from are used. Another class of vectors uses RNA elements derived from RNA viruses, such as Semeriki Forest virus, eastern equine encephalitis virus and flavivirus.

Additionally, cells that stably integrate DNA into the chromosome can be selected by introducing one or more markers that allow for the selection of transfected host cells. Markers can provide, for example, prototrophy to auxotrophic hosts, biocide resistance (eg, antibiotics) or resistance to heavy metals, such as copper, and the like. The selectable marker gene can be directly linked to the DNA sequence to be expressed, or can be introduced into the same cell by cotransformation. Additional elements may also be needed for optimal synthesis of mRNA. These elements can include splice signals, as well as transcriptional promoters, enhancers and termination signals.

Once the expression vector or DNA sequence containing the construct is prepared for expression, the expression vector can be transfected or introduced into an appropriate host cell. Various techniques can be used to achieve this, for example protoplast fusion, calcium phosphate precipitation, electroporation, retroviral transduction, viral transfection, gene gun, lipid based transfection or other conventional techniques. In the case of protoplast fusion, cells are grown in medium and screened for appropriate activity. Methods and conditions for culturing the resulting transfected cells and recovering the produced antibody molecules are known to those skilled in the art and are modified according to the specific expression vector and mammalian host cells used based on the present specification. Or it can be optimized.

In certain embodiments, the host cell comprises a nucleic acid encoding an anti-LAG-3 antibody molecule described herein. In other embodiments, the host cell is genetically engineered to include nucleic acids encoding anti-LAG-3 antibody molecules.

In one embodiment, the host cell is genetically engineered by using an expression cassette. The phrase “expression cassette” refers to a nucleotide sequence, which is capable of affecting the expression of a gene in a host compatible with this sequence. Such cassettes can include promoters, open reading frames with or without introns, and termination signals. Additional factors necessary or helpful to influence expression, such as, for example, inducible promoters, can also be used. In certain embodiments, the host cell comprises a vector described herein.

The cells can be, but are not limited to, eukaryotic cells, bacterial cells, insect cells, or human cells. Suitable eukaryotic cells include, but are not limited to, Vero cells, HeLa cells, COS cells, CHO cells, HEK293 cells, BHK cells and MDCKII cells. Suitable insect cells include, but are not limited to, Sf9 cells.

In some embodiments, the host cell is a eukaryotic cell, such as a mammalian cell, an insect cell, a yeast cell, or a prokaryotic cell, such as E. It is coli. For example, the mammalian cells can be cultured cells or cell lines. Exemplary mammalian cells include lymphocytic cell lines (eg, NSO), Chinese hamster ovary cells (CHO), COS cells, oocytes, and cells from transgenic animals, eg, breast epithelial cells.

Example

The following examples are presented to aid the understanding of the present invention, but are not intended to limit the scope of the present invention in any way and should not be construed as limiting it.

Example 1: Population pharmacokinetics and pharmacodynamics of exemplary anti-LAG-3 antibodies and soluble LAG-3

summary

The purpose of this study was to predict the relationship between serum anti-LAG-3 antibody concentration and LAG-3 occupancy in serum (soluble LAG-3) and tumor (membrane-bound LAG-3); Evaluate the relationship between anti-LAG-3 antibody dose and pharmacokinetics (PK), and whether PK variability is dose dependent; Assess the expected variability at anti-LAG-3 steady state trough levels from fixed and weight-based administration; To assess whether co-administration of anti-PD-1 antibodies affects anti-LAG-3 antibody exposure.

The following method was used in this study. Anti-LAG-3 antibody concentrations were described using a two-compartment, linear population PK model. Soluble LAG-3 data was described using a standard binding model to describe target mediated drug batches; A quasi-equilibrium approximation was used. Covariate analysis was used to estimate the effect of body weight on both clearance and central and peripheral volumes. Graph analysis was used to evaluate the effect of co-administration of anti-PD-1 antibody on anti-LAG-3 antibody clearance. Model simulations were then performed to confirm the relationship between anti-LAG-3 antibody dose and free LAG-3 for both soluble LAG-3 in serum and membrane-bound LAG-3 in tumor.

The following results were obtained from this study. The relationship between dose and free LAG-3 in serum and tumors was characterized. The anti-LAG-3 antibody PK appeared non-linear at doses less than 80 mg every 2-4 weeks and linear at doses greater than 240 mg every 3-4 weeks. Fixed and weight-based dosing regimens were expected to provide the lowest concentration of comparable variability at steady state. No apparent effect of co-administration with anti-PD-1 antibody on anti-LAG-3 antibody PK was observed.

The relationship between the anti-LAG-3 antibody dose, and the receptor share of both serum soluble LAG-3 and intratumoral membrane-bound LAG-3 receptor share at doses of 240 mg and above is well characterized by the model. Became. At lower doses (eg 80 mg every 2-4 weeks), nonlinearity of anti-LAG-3 antibody PK was observed in some patients. Above 240 mg every 3-4 weeks, the anti-LAG-3 antibody PK appeared linear. Nonlinearity is believed to be due to target mediated drug placement, as observed for many other monoclonal antibodies. Fixed and weight-based administration was predicted to provide comparable variability at steady state trough levels of anti-LAG-3 antibodies. Co-administration of anti-PD-1 antibody showed no apparent effect on anti-LAG-3 antibody PK.

The observations illustrated in this example can be used to guide dose selection for anti-LAG-3 antibody molecules described herein.

data

This study used data from a dose escalation study in patients with advanced solid tumors, in which the exemplary anti-LAG-3 antibody, LAG525 as monotherapy as well as in combination with the exemplary anti-PD-1 antibody, PDR001 Provided. Anti-LAG-3 antibody concentrations and soluble LAG-3 concentrations were measured at various times (pre-infusion, first hour, day 1, day 7, day 10, day 14).

The anti-LAG-3 antibody was quantified by liquid chromatography mass spectrometry (LC / MS), and the lower limit of quantitation was 250 ng / ml (1.7 nM). Total soluble LAG-3 was quantified by enzyme-linked immunosorbent assay (ELISA) in human serum, and the lower limit of quantitation was 0.146 ng / ml (1 pM).

A single dataset was generated and verified at the most critical level. All anti-LAG-3 antibodies and soluble LAG-3 measurements were included in this analysis. No data were excluded or classified as outliers.

Way

This study was conducted using a nonlinear mixed-effects modeling approach, where the model has two categories: a structural model that describes systematic trends in the data and a random effects model that describes both inter-subject variability and the rest of the variability for those trends. . The covariate model describes how covariates are incorporated. The PopPKPD model was simultaneously fitted to both PK and soluble LAG-3 data. Model simulations were then performed under further assumptions to make predictions for membrane-bound LAG-3 inhibition in tumors.

Analysis was performed using a Monolix software system, version 2016R1, using a MODESIM high performance computing environment. The technical computing package R was used to investigate the data, assist in building the model, and report the final results.

A number of models were investigated in the first analysis of this data, but only a single structural model was used because it was found that these models were sufficient to meet the objectives.

Structural model. Structural PKPD models for anti-LAG-3, soluble LAG-3, and complex concentrations are standard binding models used to describe target-mediated drug placement (TMDD) as a quasi-equilibrium approximation (Mager & Krzyzanski. Pharmaceutical Research 22, 1589-1596 (2005)), the differential equation describes the total drug, total target, and peripheral drug concentrations, and the following algebraic expression is used to calculate free drug, free target, and complex concentrations.

The Michaelis-Menten version of this model was also fitted. In exploratory analysis, this model did not improve the fit and therefore was not further investigated.

Random effect model. The PK model was parameterized by the following four parameters: clearance, central volume, peripheral volume, and inter-compartment clearance, and the PD (soluble LAG-3) model added the following four parameters: initial sLAG-3, large capacity Steady-state sLAG-3, antibody-sLAG-3 complex removal rate, and dissociation constant for the anti-LAG-3 antibody. A lognormal random effect was added to all 8 parameters.

Covariate model. Covariate analysis was used to evaluate the effect of body weight on clearance and central volume. Using graph analysis, anti-LAG-3 antibody PKs are compared by comparing anti-LAG-3 antibody concentrations in patients receiving or not receiving the same anti-LAG-3 antibody dosing regimen. The effect of anti-PD-1 antibody on was evaluated. No formal covariate analysis was performed because the patient had the fastest clearance rate at the lowest anti-LAG-3 antibody dose (0.3 mg / kg q2w) and was always given an anti-PD-1 antibody. Faster elimination at the lowest dose is thought to be due to targeted drug placement, but this effect has been observed to confuse the formal assessment of anti-PD-1 antibodies as a covariate for clearance.

Comparison of fixed and weight scaled dosing regimens. The lowest level of anti-LAG-3 antibody at week 24 (approximately 6 months) was simulated using a 10 mg / kg or 700 mg model given every 2, 3, or 4 weeks for 1000 patients. Preliminary model pits showed that the terminal half-life of the anti-LAG-3 antibody was about 2 weeks, so all patients were expected to be normal at Week 24; In addition, Week 24 was the lowest for all dosing regimens tested (q2w, q3w, q4w). Median and 95% predicted interval values were plotted. A typical patient's body weight was assumed to be 80 kg (eg 1 mg / kg corresponds to 80 mg) so that an equivalent fixed dose regimen could be calculated. However, the median weight in the population of this study was closer to 70 kg. For this reason, for this particular simulation, 10 mg / kg was compared to 700 mg.

Prediction of LAG-3 inhibition in serum and tumors. Using the simulation from the PKPD model, the LAG-3 occupancy was estimated at the lowest level at 6 months, when PK was normal. Two different LAG-3 occupancy estimates were provided: (1) Ratio of free soluble LAG-3 in serum compared to baseline soluble LAG-3, calculated directly from the PKPD model; And (2) the share of membrane-bound LAG-3 in the tumor (RO).

The prediction for intratumoral LAG-3 inhibition is thought to be more appropriate to guide dose selection as it is the site where tumor-infiltrating lymphocytes interact with the tumor.

Using this approach to predict target occupancy in tumors entails numerous assumptions: (1) The estimated dissociation constant of anti-LAG-3 antibody against sLAG-3 in serum is membrane-bound LAG-3 in tumor. Same as dissociation of anti-LAG-3 antibody against; (2) Based on mouse data (Deng et al. MAbs, vol. 8, 593-603 (2016)), such ABC _ISF = 30% in human tumors; (3) tumors can be treated with homogeneous tissue; (4) membrane-bound LAG-3 in the tumor does not accumulate in the presence of the drug; (5) the anti-LAG-3 antibody was excessively excess compared to the membrane-bound LAG-3 concentration in the tumor; And (6) the binding between LAG-3 and its endogenous binding partner (eg MHCII) is not modeled, and it is assumed that it does not significantly affect the prediction of inhibition.

In addition to these assumptions, the desired level of inhibition for the desired fraction of the patient population should be selected. Typically, 60-90% inhibition is required for antagonists, so 90-95% occupancy is targeted for this analysis (Grimwood & Hartig. Pharmacology & Therapeutics 122, 281-301 (2009); Tiwari et al. The AAPS Journal 1-10 (2016); Agoram.British Journal of Clinical Pharmacology 67, 153-160 (2009)).

For these test simulations, the following doses were tested with q2w, q3w, and q4w therapy for 1000 patients: 10, 20, 30, 50, 70, 100, 200, 300, 400, 500, 600, 700, 800 , 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000 mg. The 5, 25, 50, 75, and 95 percentiles were then calculated for soluble LAG-3 occupancy in PK, and serum and membrane-bound LAG-3 occupancy in tumors.

result

A total of 196 patients were included in this analysis and median follow-up time was 30 and 29.5 days, respectively, for anti-LAG-3 antibody and soluble-LAG-3 evaluations. A summary of the number of patients for each dosing regimen, sorted by total 1 month dose (average total dose over 4 weeks), is presented in Table 13.

Table 13. Summary of dosing regimens and number of patients

Anti-LAG-3 antibody and soluble LAG-3 data were obtained. Anti-LAG-3 antibody concentration data for the first 4 weeks was normalized by the first dose (mg). Anti-LAG-3 antibody doses were stratified into 4 groups (very low, low, medium, and high) based on the estimated total 1 month dose (over 28 days, in mg). For body weighted doses, the total mg dose was calculated for 80 kg patients. Larger reductions in anti-LAG-3 antibody concentrations were observed in some patients for very low and low dose data than the medium and high dose data, indicating nonlinear PK at lower doses. The stratified group was selected to illustrate this nonlinearity.

Normalized anti-LAG-3 antibody concentration (all therapies) 2 weeks after the first dose was obtained. At lower doses (up to 80 mg) there was a decrease in normalized drug concentration in some patients, indicating nonlinearity in PK. Model-based analysis of data can also help better characterize this nonlinearity using all available data.

PKPD model feet

The PK parameters used were typical for monoclonal antibodies. By simulating the parameters, the terminal half-life and its 5-95% prediction interval were estimated to be 17.0 (7.0, 59.9) days. The estimated dissociation constant of 1.5 nM (Kd) was higher than that measured in the Biacore assay (0.1 nM), but was comparable to that measured in the in vitro cell-based assay (1.9-2.3 nM). Visual predictive investigation of the anti-LAG-3 antibody concentration normalized by the total 1 month dose showed a good description of PK data except for the low and very low dose groups where PK nonlinearity was observed. A simulation of the largest anti-LAG-3 antibody dose within each panel was performed. The simulation well explained the sLAG-3 curve for all doses q4w greater than 3 mg / kg (or 240 mg). For low dose data, PK was overestimated, so sLAG-3 was also overestimated.

In view of faster removal at lower doses, the Michaelis-Menten PK model with nonlinear removal was previously studied. However, Pete was not significantly better. In addition, the additive error was generally estimated to be about 20 nM, much greater than the lowest concentration observed at 0.3 mg / kg q2w or 80 mg q4w, even for models with nonlinear removal. Therefore, in this example, only the linear model was used under the risk that the model overestimated the lowest concentration at a lower dose (eg 80 mg q2w).

Anti-LAG-3 antibody population predictions vs. measurements were examined to establish a threshold at which nonlinearity began to be involved in PK. At critical concentrations C _crit = less than 60 nM, the population predictions overestimate the measurements; Note that it is less than the C _crit that nonlinear PK begins to be observed. Using a test simulation, the fraction of patients expected to remain above the C _crit at the lowest was estimated in Table 14.

Fixed vs weight-based dosing prediction

Simulations of the lowest level of anti-LAG-3 antibody at 6 months for 700 mg and 10 mg / kg administration were performed for both fixed and weight-scaled administration. Because the weight-related index for clearance was close to 0.5, the predicted variability at the anti-LAG-3 antibody knockdown was comparable for patients receiving fixed or weight-based administration, as also observed for other drugs ( Bai et al. Clinical pharmacokinetics 51, 119-135 (2012); Wang et al., The Journal of Clinical Pharmacology 49, 1012-1024 (2009)). Since the anti-LAG-3 antibody PK model is linear at> 240 mg, similar results will be observed for any dose above 240 mg.

LAG-3 market share forecast

The simulated free LAG-3 concentration was compared to the baseline from the PKPD model. Recall that this model did not capture the non-linearity in the PK observed at lower doses, and thus less likely to have LAG-3 inhibition than predicted at doses below 240 mg. Reducing free soluble LAG-3 to 10% requires a dose higher than 10x than to reduce intratumoral membrane-bound LAG-3 to 10%. This is because soluble LAG-3 accumulates about 75x in serum, while membrane-bound LAG-3 is not expected to accumulate.

The results from this simulation are summarized in Table 14, where the doses required for 75, 90, and 95% of patients to meet the following three criteria at steady state are summarized:

1.Lowest LAG525 exceeding C _crit

2. Tumors less than 10% of baseline, membrane-bound LAG-3 free receptor

3. Serum soluble LAG-3 free receptor less than 10% of baseline

Table 14. Predicted doses (mg) required for 75%, 90%, and 95% of patients at steady state to meet the specified PK or PD criteria under q2w, q3w, and q4w therapy

Note that the dose required for linear PK (lowest anti-LAG-3 antibody> C _crit ) and the dose required to reduce free tumor mLAG-3 concentration to <10% from baseline are similar. These results are consistent with the hypothesis that targeted drug placement by tumor infiltrating lymphocytes drives rapid clearance at lower doses.

For antagonists, it is typical to target 90-95% receptor occupancy (or 5-10% free target compared to baseline) throughout the dosing interval, but this rule of thumb is generally for LAG-3 or immune checkpoint inhibitors. Not verified In cases where the goal is to achieve this receptor occupancy in most patients, it will be important to provide sufficient doses so that rapid clearance at lower concentrations is not observed. Visual predictive investigation of anti-LAG-3 antibody concentration normalized by the total 1 month dose suggests that doses exceeding 240 mg q4w may be sufficient to avoid this nonlinearity. Table 14 predicts that 400 mg q3w or 800 mg q4w will provide 90% to 90% receptor occupancy (10% free LAG-3 vs baseline) in patients.

Thus, this study investigated receptor occupancy of both the exemplary anti-LAG-3 antibody, the dose of LAG525, and the serum soluble LAG-3 and intratumoral membrane-bound LAG-3 receptor occupancy at doses of 240 mg and beyond. The relationship between them is well characterized by the model. At lower doses (eg 80 mg every 2-4 weeks), nonlinearity was observed in the anti-LAG-3 antibody PK in some patients. Above 240 mg every 3-4 weeks, the anti-LAG-3 antibody PK appeared linear. Nonlinearity is believed to be due to target mediated drug placement, as observed for many other monoclonal antibodies. Fixed and weight-based administration was predicted to provide comparable variability at steady state trough levels of anti-LAG-3 antibodies. Co-administration of the anti-PD-1 antibody, PDR001, showed no apparent effect on the anti-LAG-3 antibody PK.

Include as reference

All publications, patents, and accession numbers mentioned herein are incorporated herein by reference in their entirety, as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.

Equivalent

Although specific embodiments of the invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by referring to the claims together with their full equivalent categories and the specification with reference to these modifications.

                               SEQUENCE LISTING <110> NOVARTIS AG   <120> DOSAGE REGIMENS FOR ANTI-LAG-3 ANTIBODIES AND USES THEREOF <130> C2160-7019WO <140> <141> <150> 62 / 534,798 <151> 2017-07-20 <150> 62 / 643,992 <151> 2018-03-16 <160> 1006 <170> PatentIn version 3.5 <210> 1 <400> 1 000 <210> 2 <400> 2 000 <210> 3 <400> 3 000 <210> 4 <400> 4 000 <210> 5 <400> 5 000 <210> 6 <400> 6 000 <210> 7 <400> 7 000 <210> 8 <400> 8 000 <210> 9 <400> 9 000 <210> 10 <400> 10 000 <210> 11 <400> 11 000 <210> 12 <400> 12 000 <210> 13 <400> 13 000 <210> 14 <400> 14 000 <210> 15 <400> 15 000 <210> 16 <400> 16 000 <210> 17 <400> 17 000 <210> 18 <400> 18 000 <210> 19 <400> 19 000 <210> 20 <400> 20 000 <210> 21 <400> 21 000 <210> 22 <400> 22 000 <210> 23 <400> 23 000 <210> 24 <400> 24 000 <210> 25 <400> 25 000 <210> 26 <400> 26 000 <210> 27 <400> 27 000 <210> 28 <400> 28 000 <210> 29 <400> 29 000 <210> 30 <400> 30 000 <210> 31 <400> 31 000 <210> 32 <400> 32 000 <210> 33 <400> 33 000 <210> 34 <400> 34 000 <210> 35 <400> 35 000 <210> 36 <400> 36 000 <210> 37 <400> 37 000 <210> 38 <400> 38 000 <210> 39 <400> 39 000 <210> 40 <400> 40 000 <210> 41 <400> 41 000 <210> 42 <400> 42 000 <210> 43 <400> 43 000 <210> 44 <400> 44 000 <210> 45 <400> 45 000 <210> 46 <400> 46 000 <210> 47 <400> 47 000 <210> 48 <400> 48 000 <210> 49 <400> 49 000 <210> 50 <400> 50 000 <210> 51 <400> 51 000 <210> 52 <400> 52 000 <210> 53 <400> 53 000 <210> 54 <400> 54 000 <210> 55 <400> 55 000 <210> 56 <400> 56 000 <210> 57 <400> 57 000 <210> 58 <400> 58 000 <210> 59 <400> 59 000 <210> 60 <400> 60 000 <210> 61 <400> 61 000 <210> 62 <400> 62 000 <210> 63 <400> 63 000 <210> 64 <400> 64 000 <210> 65 <400> 65 000 <210> 66 <400> 66 000 <210> 67 <400> 67 000 <210> 68 <400> 68 000 <210> 69 <400> 69 000 <210> 70 <400> 70 000 <210> 71 <400> 71 000 <210> 72 <400> 72 000 <210> 73 <400> 73 000 <210> 74 <400> 74 000 <210> 75 <400> 75 000 <210> 76 <400> 76 000 <210> 77 <400> 77 000 <210> 78 <400> 78 000 <210> 79 <400> 79 000 <210> 80 <400> 80 000 <210> 81 <400> 81 000 <210> 82 <400> 82 000 <210> 83 <400> 83 000 <210> 84 <400> 84 000 <210> 85 <400> 85 000 <210> 86 <400> 86 000 <210> 87 <400> 87 000 <210> 88 <400> 88 000 <210> 89 <400> 89 000 <210> 90 <400> 90 000 <210> 91 <400> 91 000 <210> 92 <400> 92 000 <210> 93 <400> 93 000 <210> 94 <400> 94 000 <210> 95 <400> 95 000 <210> 96 <400> 96 000 <210> 97 <400> 97 000 <210> 98 <400> 98 000 <210> 99 <400> 99 000 <210> 100 <400> 100 000 <210> 101 <400> 101 000 <210> 102 <400> 102 000 <210> 103 <400> 103 000 <210> 104 <400> 104 000 <210> 105 <400> 105 000 <210> 106 <400> 106 000 <210> 107 <400> 107 000 <210> 108 <400> 108 000 <210> 109 <400> 109 000 <210> 110 <400> 110 000 <210> 111 <400> 111 000 <210> 112 <400> 112 000 <210> 113 <400> 113 000 <210> 114 <400> 114 000 <210> 115 <400> 115 000 <210> 116 <400> 116 000 <210> 117 <400> 117 000 <210> 118 <400> 118 000 <210> 119 <400> 119 000 <210> 120 <400> 120 000 <210> 121 <400> 121 000 <210> 122 <400> 122 000 <210> 123 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<210> 373 <400> 373 000 <210> 374 <400> 374 000 <210> 375 <400> 375 000 <210> 376 <400> 376 000 <210> 377 <400> 377 000 <210> 378 <400> 378 000 <210> 379 <400> 379 000 <210> 380 <400> 380 000 <210> 381 <400> 381 000 <210> 382 <400> 382 000 <210> 383 <400> 383 000 <210> 384 <400> 384 000 <210> 385 <400> 385 000 <210> 386 <400> 386 000 <210> 387 <400> 387 000 <210> 388 <400> 388 000 <210> 389 <400> 389 000 <210> 390 <400> 390 000 <210> 391 <400> 391 000 <210> 392 <400> 392 000 <210> 393 <400> 393 000 <210> 394 <400> 394 000 <210> 395 <400> 395 000 <210> 396 <400> 396 000 <210> 397 <400> 397 000 <210> 398 <400> 398 000 <210> 399 <400> 399 000 <210> 400 <400> 400 000 <210> 401 <400> 401 000 <210> 402 <400> 402 000 <210> 403 <400> 403 000 <210> 404 <400> 404 000 <210> 405 <400> 405 000 <210> 406 <400> 406 000 <210> 407 <400> 407 000 <210> 408 <400> 408 000 <210> 409 <400> 409 000 <210> 410 <400> 410 000 <210> 411 <400> 411 000 <210> 412 <400> 412 000 <210> 413 <400> 413 000 <210> 414 <400> 414 000 <210> 415 <400> 415 000 <210> 416 <400> 416 000 <210> 417 <400> 417 000 <210> 418 <400> 418 000 <210> 419 <400> 419 000 <210> 420 <400> 420 000 <210> 421 <400> 421 000 <210> 422 <400> 422 000 <210> 423 <400> 423 000 <210> 424 <400> 424 000 <210> 425 <400> 425 000 <210> 426 <400> 426 000 <210> 427 <400> 427 000 <210> 428 <400> 428 000 <210> 429 <400> 429 000 <210> 430 <400> 430 000 <210> 431 <400> 431 000 <210> 432 <400> 432 000 <210> 433 <400> 433 000 <210> 434 <400> 434 000 <210> 435 <400> 435 000 <210> 436 <400> 436 000 <210> 437 <400> 437 000 <210> 438 <400> 438 000 <210> 439 <400> 439 000 <210> 440 <400> 440 000 <210> 441 <400> 441 000 <210> 442 <400> 442 000 <210> 443 <400> 443 000 <210> 444 <400> 444 000 <210> 445 <400> 445 000 <210> 446 <400> 446 000 <210> 447 <400> 447 000 <210> 448 <400> 448 000 <210> 449 <400> 449 000 <210> 450 <400> 450 000 <210> 451 <400> 451 000 <210> 452 <400> 452 000 <210> 453 <400> 453 000 <210> 454 <400> 454 000 <210> 455 <400> 455 000 <210> 456 <400> 456 000 <210> 457 <400> 457 000 <210> 458 <400> 458 000 <210> 459 <400> 459 000 <210> 460 <400> 460 000 <210> 461 <400> 461 000 <210> 462 <400> 462 000 <210> 463 <400> 463 000 <210> 464 <400> 464 000 <210> 465 <400> 465 000 <210> 466 <400> 466 000 <210> 467 <400> 467 000 <210> 468 <400> 468 000 <210> 469 <400> 469 000 <210> 470 <400> 470 000 <210> 471 <400> 471 000 <210> 472 <400> 472 000 <210> 473 <400> 473 000 <210> 474 <400> 474 000 <210> 475 <400> 475 000 <210> 476 <400> 476 000 <210> 477 <400> 477 000 <210> 478 <400> 478 000 <210> 479 <400> 479 000 <210> 480 <400> 480 000 <210> 481 <400> 481 000 <210> 482 <400> 482 000 <210> 483 <400> 483 000 <210> 484 <400> 484 000 <210> 485 <400> 485 000 <210> 486 <400> 486 000 <210> 487 <400> 487 000 <210> 488 <400> 488 000 <210> 489 <400> 489 000 <210> 490 <400> 490 000 <210> 491 <400> 491 000 <210> 492 <400> 492 000 <210> 493 <400> 493 000 <210> 494 <400> 494 000 <210> 495 <400> 495 000 <210> 496 <400> 496 000 <210> 497 <400> 497 000 <210> 498 <400> 498 000 <210> 499 <400> 499 000 <210> 500 <400> 500 000 <210> 501 <211> 5 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 501 Thr Tyr Trp Met His 1 5 <210> 502 <211> 17 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 502 Asn Ile Tyr Pro Gly Thr Gly Gly Ser Asn Phe Asp Glu Lys Phe Lys 1 5 10 15 Asn      <210> 503 <211> 8 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 503 Trp Thr Thr Gly Thr Gly Ala Tyr 1 5 <210> 504 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 504 Gly Tyr Thr Phe Thr Thr Tyr 1 5 <210> 505 <211> 6 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 505 Tyr Pro Gly Thr Gly Gly 1 5 <210> 506 <211> 117 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 506 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Thr Tyr             20 25 30 Trp Met His Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met         35 40 45 Gly Asn Ile Tyr Pro Gly Thr Gly Gly Ser Asn Phe Asp Glu Lys Phe     50 55 60 Lys Asn Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Thr Arg Trp Thr Thr Gly Thr Gly Ala Tyr Trp Gly Gln Gly Thr Thr             100 105 110 Val Thr Val Ser Ser         115 <210> 507 <211> 351 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 507 gaggtgcagc tggtgcagtc aggcgccgaa gtgaagaagc ccggcgagtc actgagaatt 60 agctgtaaag gttcaggcta caccttcact acctactgga tgcactgggt ccgccaggct 120 accggtcaag gcctcgagtg gatgggtaat atctaccccg gcaccggcgg ctctaacttc 180 gacgagaagt ttaagaatag agtgactatc accgccgata agtctactag caccgcctat 240 atggaactgt ctagcctgag atcagaggac accgccgtct actactgcac taggtggact 300 accggcacag gcgcctactg gggtcaaggc actaccgtga ccgtgtctag c 351 <210> 508 <211> 443 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 508 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Thr Tyr             20 25 30 Trp Met His Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met         35 40 45 Gly Asn Ile Tyr Pro Gly Thr Gly Gly Ser Asn Phe Asp Glu Lys Phe     50 55 60 Lys Asn Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Thr Arg Trp Thr Thr Gly Thr Gly Ala Tyr Trp Gly Gln Gly Thr Thr             100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu         115 120 125 Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys     130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser                 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser             180 185 190 Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn         195 200 205 Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro     210 215 220 Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe 225 230 235 240 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val                 245 250 255 Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe             260 265 270 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro         275 280 285 Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr     290 295 300 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320 Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala                 325 330 335 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln             340 345 350 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly         355 360 365 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro     370 375 380 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 385 390 395 400 Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu                 405 410 415 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His             420 425 430 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly         435 440 <210> 509 <211> 1329 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 509 gaggtgcagc tggtgcagtc aggcgccgaa gtgaagaagc ccggcgagtc actgagaatt 60 agctgtaaag gttcaggcta caccttcact acctactgga tgcactgggt ccgccaggct 120 accggtcaag gcctcgagtg gatgggtaat atctaccccg gcaccggcgg ctctaacttc 180 gacgagaagt ttaagaatag agtgactatc accgccgata agtctactag caccgcctat 240 atggaactgt ctagcctgag atcagaggac accgccgtct actactgcac taggtggact 300 accggcacag gcgcctactg gggtcaaggc actaccgtga ccgtgtctag cgctagcact 360 aagggcccgt ccgtgttccc cctggcacct tgtagccgga gcactagcga atccaccgct 420 gccctcggct gcctggtcaa ggattacttc ccggagcccg tgaccgtgtc ctggaacagc 480 ggagccctga cctccggagt gcacaccttc cccgctgtgc tgcagagctc cgggctgtac 540 tcgctgtcgt cggtggtcac ggtgccttca tctagcctgg gtaccaagac ctacacttgc 600 aacgtggacc acaagccttc caacactaag gtggacaagc gcgtcgaatc gaagtacggc 660 ccaccgtgcc cgccttgtcc cgcgccggag ttcctcggcg gtccctcggt ctttctgttc 720 ccaccgaagc ccaaggacac tttgatgatt tcccgcaccc ctgaagtgac atgcgtggtc 780 gtggacgtgt cacaggaaga tccggaggtg cagttcaatt ggtacgtgga tggcgtcgag 840 gtgcacaacg ccaaaaccaa gccgagggag gagcagttca actccactta ccgcgtcgtg 900 tccgtgctga cggtgctgca tcaggactgg ctgaacggga aggagtacaa gtgcaaagtg 960 tccaacaagg gacttcctag ctcaatcgaa aagaccatct cgaaagccaa gggacagccc 1020 cgggaacccc aagtgtatac cctgccaccg agccaggaag aaatgactaa gaaccaagtc 1080 tcattgactt gccttgtgaa gggcttctac ccatcggata tcgccgtgga atgggagtcc 1140 aacggccagc cggaaaacaa ctacaagacc acccctccgg tgctggactc agacggatcc 1200 ttcttcctct actcgcggct gaccgtggat aagagcagat ggcaggaggg aaatgtgttc 1260 agctgttctg tgatgcatga agccctgcac aaccactaca ctcagaagtc cctgtccctc 1320 tccctggga 1329 <210> 510 <211> 17 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 510 Lys Ser Ser Gln Ser Leu Leu Asp Ser Gly Asn Gln Lys Asn Phe Leu 1 5 10 15 Thr      <210> 511 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 511 Trp Ala Ser Thr Arg Glu Ser 1 5 <210> 512 <211> 9 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 512 Gln Asn Asp Tyr Ser Tyr Pro Tyr Thr 1 5 <210> 513 <211> 13 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 513 Ser Gln Ser Leu Leu Asp Ser Gly Asn Gln Lys Asn Phe 1 5 10 <210> 514 <211> 3 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 514 Trp Ala Ser One <210> 515 <211> 6 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 515 Asp Tyr Ser Tyr Pro Tyr 1 5 <210> 516 <211> 113 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 516 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser             20 25 30 Gly Asn Gln Lys Asn Phe Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys         35 40 45 Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val     50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr 65 70 75 80 Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Asn                 85 90 95 Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile             100 105 110 Lys      <210> 517 <211> 339 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 517 gagatcgtcc tgactcagtc acccgctacc ctgagcctga gccctggcga gcgggctaca 60 ctgagctgta aatctagtca gtcactgctg gatagcggta atcagaagaa cttcctgacc 120 tggtatcagc agaagcccgg taaagcccct aagctgctga tctactgggc ctctactaga 180 gaatcaggcg tgccctctag gtttagcggt agcggtagtg gcaccgactt caccttcact 240 atctctagcc tgcagcccga ggatatcgct acctactact gtcagaacga ctatagctac 300 ccctacacct tcggtcaagg cactaaggtc gagattaag 339 <210> 518 <211> 220 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 518 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser             20 25 30 Gly Asn Gln Lys Asn Phe Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys         35 40 45 Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val     50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr 65 70 75 80 Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Asn                 85 90 95 Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile             100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp         115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn     130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp                 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr             180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser         195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys     210 215 220 <210> 519 <211> 660 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 519 gagatcgtcc tgactcagtc acccgctacc ctgagcctga gccctggcga gcgggctaca 60 ctgagctgta aatctagtca gtcactgctg gatagcggta atcagaagaa cttcctgacc 120 tggtatcagc agaagcccgg taaagcccct aagctgctga tctactgggc ctctactaga 180 gaatcaggcg tgccctctag gtttagcggt agcggtagtg gcaccgactt caccttcact 240 atctctagcc tgcagcccga ggatatcgct acctactact gtcagaacga ctatagctac 300 ccctacacct tcggtcaagg cactaaggtc gagattaagc gtacggtggc cgctcccagc 360 gtgttcatct tcccccccag cgacgagcag ctgaagagcg gcaccgccag cgtggtgtgc 420 ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt ggaaggtgga caacgccctg 480 cagagcggca acagccagga gagcgtcacc gagcaggaca gcaaggactc cacctacagc 540 ctgagcagca ccctgaccct gagcaaggcc gactacgaga agcataaggt gtacgcctgc 600 gaggtgaccc accagggcct gtccagcccc gtgaccaaga gcttcaacag gggcgagtgc 660 <210> 520 <211> 113 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 520 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser             20 25 30 Gly Asn Gln Lys Asn Phe Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln         35 40 45 Ala Pro Arg Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val     50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr 65 70 75 80 Ile Ser Ser Leu Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Asn                 85 90 95 Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile             100 105 110 Lys      <210> 521 <211> 339 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 521 gagatcgtcc tgactcagtc acccgctacc ctgagcctga gccctggcga gcgggctaca 60 ctgagctgta aatctagtca gtcactgctg gatagcggta atcagaagaa cttcctgacc 120 tggtatcagc agaagcccgg tcaagcccct agactgctga tctactgggc ctctactaga 180 gaatcaggcg tgccctctag gtttagcggt agcggtagtg gcaccgactt caccttcact 240 atctctagcc tggaagccga ggacgccgct acctactact gtcagaacga ctatagctac 300 ccctacacct tcggtcaagg cactaaggtc gagattaag 339 <210> 522 <211> 220 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 522 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser             20 25 30 Gly Asn Gln Lys Asn Phe Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln         35 40 45 Ala Pro Arg Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val     50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr 65 70 75 80 Ile Ser Ser Leu Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Asn                 85 90 95 Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile             100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp         115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn     130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp                 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr             180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser         195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys     210 215 220 <210> 523 <211> 660 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 523 gagatcgtcc tgactcagtc acccgctacc ctgagcctga gccctggcga gcgggctaca 60 ctgagctgta aatctagtca gtcactgctg gatagcggta atcagaagaa cttcctgacc 120 tggtatcagc agaagcccgg tcaagcccct agactgctga tctactgggc ctctactaga 180 gaatcaggcg tgccctctag gtttagcggt agcggtagtg gcaccgactt caccttcact 240 atctctagcc tggaagccga ggacgccgct acctactact gtcagaacga ctatagctac 300 ccctacacct tcggtcaagg cactaaggtc gagattaagc gtacggtggc cgctcccagc 360 gtgttcatct tcccccccag cgacgagcag ctgaagagcg gcaccgccag cgtggtgtgc 420 ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt ggaaggtgga caacgccctg 480 cagagcggca acagccagga gagcgtcacc gagcaggaca gcaaggactc cacctacagc 540 ctgagcagca ccctgaccct gagcaaggcc gactacgaga agcataaggt gtacgcctgc 600 gaggtgaccc accagggcct gtccagcccc gtgaccaaga gcttcaacag gggcgagtgc 660 <210> 524 <211> 15 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 524 acctactgga tgcac 15 <210> 525 <211> 51 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 525 aatatctacc ccggcaccgg cggctctaac ttcgacgaga agtttaagaa t 51 <210> 526 <211> 24 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 526 tggactaccg gcacaggcgc ctac 24 <210> 527 <211> 21 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 527 ggctacacct tcactaccta c 21 <210> 528 <211> 18 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 528 taccccggca ccggcggc 18 <210> 529 <211> 51 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 529 aaatctagtc agtcactgct ggatagcggt aatcagaaga acttcctgac c 51 <210> 530 <211> 21 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 530 tgggcctcta ctagagaatc a 21 <210> 531 <211> 27 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 531 cagaacgact atagctaccc ctacacc 27 <210> 532 <211> 39 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 532 agtcagtcac tgctggatag cggtaatcag aagaacttc 39 <210> 533 <211> 9 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 533 tgggcctct 9 <210> 534 <211> 18 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 534 gactatagct acccctac 18 <210> 535 <211> 440 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 535 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser             20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser             100 105 110 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser         115 120 125 Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp     130 135 140 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 145 150 155 160 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr                 165 170 175 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys             180 185 190 Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp         195 200 205 Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala     210 215 220 Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 225 230 235 240 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val                 245 250 255 Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val             260 265 270 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln         275 280 285 Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln     290 295 300 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 305 310 315 320 Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro                 325 330 335 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr             340 345 350 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser         355 360 365 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr     370 375 380 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 385 390 395 400 Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe                 405 410 415 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys             420 425 430 Ser Leu Ser Leu Ser Leu Gly Lys         435 440 <210> 536 <211> 214 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 536 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr             20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile         35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly     50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg                 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala             100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly         115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala     130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser                 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr             180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser         195 200 205 Phe Asn Arg Gly Glu Cys     210 <210> 537 <211> 447 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 537 Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr             20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met         35 40 45 Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe     50 55 60 Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr 65 70 75 80 Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln             100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val         115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala     130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val                 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro             180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys         195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro     210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr                 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu             260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys         275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser     290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile                 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro             340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu         355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn     370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg                 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu             420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys         435 440 445 <210> 538 <211> 218 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 538 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser             20 25 30 Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro         35 40 45 Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala     50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg                 85 90 95 Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg             100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln         115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr     130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr                 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys             180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro         195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys     210 215 <210> 539 <211> 447 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 539 Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr             20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Gln Trp Met         35 40 45 Gly Trp Ile Asn Thr Asp Ser Gly Glu Ser Thr Tyr Ala Glu Glu Phe     50 55 60 Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Asn Thr Ala Tyr 65 70 75 80 Leu Gln Ile Thr Ser Leu Thr Ala Glu Asp Thr Gly Met Tyr Phe Cys                 85 90 95 Val Arg Val Gly Tyr Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Leu             100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu         115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys     130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser                 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser             180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn         195 200 205 Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His     210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr                 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu             260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys         275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser     290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile                 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro             340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu         355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn     370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg                 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu             420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys         435 440 445 <210> 540 <211> 213 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 540 Glu Ile Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Arg Ser Ser Val Ser Tyr Met             20 25 30 His Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp Ile Tyr         35 40 45 Arg Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser     50 55 60 Gly Ser Gly Thr Ser Tyr Cys Leu Thr Ile Asn Ser Leu Gln Pro Glu 65 70 75 80 Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Ser Phe Pro Leu Thr                 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro             100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr         115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys     130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser                 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala             180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe         195 200 205 Asn Arg Gly Glu Cys     210 <210> 541 <211> 10 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 541 Gly Tyr Thr Phe Thr Thr Tyr Trp Met His 1 5 10 <210> 542 <400> 542 000 <210> 543 <400> 543 000 <210> 544 <400> 544 000 <210> 545 <400> 545 000 <210> 546 <400> 546 000 <210> 547 <400> 547 000 <210> 548 <400> 548 000 <210> 549 <400> 549 000 <210> 550 <400> 550 000 <210> 551 <400> 551 000 <210> 552 <400> 552 000 <210> 553 <400> 553 000 <210> 554 <400> 554 000 <210> 555 <400> 555 000 <210> 556 <400> 556 000 <210> 557 <400> 557 000 <210> 558 <400> 558 000 <210> 559 <400> 559 000 <210> 560 <400> 560 000 <210> 561 <400> 561 000 <210> 562 <400> 562 000 <210> 563 <400> 563 000 <210> 564 <400> 564 000 <210> 565 <400> 565 000 <210> 566 <400> 566 000 <210> 567 <400> 567 000 <210> 568 <400> 568 000 <210> 569 <400> 569 000 <210> 570 <400> 570 000 <210> 571 <400> 571 000 <210> 572 <400> 572 000 <210> 573 <400> 573 000 <210> 574 <400> 574 000 <210> 575 <400> 575 000 <210> 576 <400> 576 000 <210> 577 <400> 577 000 <210> 578 <400> 578 000 <210> 579 <400> 579 000 <210> 580 <400> 580 000 <210> 581 <400> 581 000 <210> 582 <400> 582 000 <210> 583 <400> 583 000 <210> 584 <400> 584 000 <210> 585 <400> 585 000 <210> 586 <400> 586 000 <210> 587 <400> 587 000 <210> 588 <400> 588 000 <210> 589 <400> 589 000 <210> 590 <400> 590 000 <210> 591 <400> 591 000 <210> 592 <400> 592 000 <210> 593 <400> 593 000 <210> 594 <400> 594 000 <210> 595 <400> 595 000 <210> 596 <400> 596 000 <210> 597 <400> 597 000 <210> 598 <400> 598 000 <210> 599 <400> 599 000 <210> 600 <400> 600 000 <210> 601 <211> 5 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 601 Ser Tyr Trp Met Tyr 1 5 <210> 602 <211> 17 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 602 Arg Ile Asp Pro Asn Ser Gly Ser Thr Lys Tyr Asn Glu Lys Phe Lys 1 5 10 15 Asn      <210> 603 <211> 11 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 603 Asp Tyr Arg Lys Gly Leu Tyr Ala Met Asp Tyr 1 5 10 <210> 604 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 604 Gly Tyr Thr Phe Thr Ser Tyr 1 5 <210> 605 <211> 6 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 605 Asp Pro Asn Ser Gly Ser 1 5 <210> 606 <211> 120 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 606 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Ser Tyr             20 25 30 Trp Met Tyr Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Ile         35 40 45 Gly Arg Ile Asp Pro Asn Ser Gly Ser Thr Lys Tyr Asn Glu Lys Phe     50 55 60 Lys Asn Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Asp Tyr Arg Lys Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln             100 105 110 Gly Thr Thr Val Thr Val Ser Ser         115 120 <210> 607 <211> 360 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 607 gaagtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctac cgtgaagatt 60 agctgtaaag tctcaggcta caccttcact agctactgga tgtactgggt ccgacaggct 120 agagggcaaa gactggagtg gatcggtaga atcgacccta atagcggctc tactaagtat 180 aacgagaagt ttaagaatag gttcactatt agtagggata actctaagaa caccctgtac 240 ctgcagatga atagcctgag agccgaggac accgccgtct actactgcgc tagagactat 300 agaaagggcc tgtacgctat ggactactgg ggtcaaggca ctaccgtgac cgtgtcttca 360 <210> 608 <211> 446 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 608 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Ser Tyr             20 25 30 Trp Met Tyr Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Ile         35 40 45 Gly Arg Ile Asp Pro Asn Ser Gly Ser Thr Lys Tyr Asn Glu Lys Phe     50 55 60 Lys Asn Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Asp Tyr Arg Lys Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln             100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val         115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala     130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val                 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro             180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys         195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro     210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr                 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu             260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys         275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser     290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile                 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro             340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu         355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn     370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg                 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu             420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly         435 440 445 <210> 609 <211> 11 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 609 Lys Ala Ser Gln Asp Val Gly Thr Ala Val Ala 1 5 10 <210> 610 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 610 Trp Ala Ser Thr Arg His Thr 1 5 <210> 611 <211> 9 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 611 Gln Gln Tyr Asn Ser Tyr Pro Leu Thr 1 5 <210> 612 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 612 Ser Gln Asp Val Gly Thr Ala 1 5 <210> 613 <211> 3 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 613 Trp Ala Ser One <210> 614 <211> 6 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 614 Tyr Asn Ser Tyr Pro Leu 1 5 <210> 615 <211> 1338 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 615 gaagtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctac cgtgaagatt 60 agctgtaaag tctcaggcta caccttcact agctactgga tgtactgggt ccgacaggct 120 agagggcaaa gactggagtg gatcggtaga atcgacccta atagcggctc tactaagtat 180 aacgagaagt ttaagaatag gttcactatt agtagggata actctaagaa caccctgtac 240 ctgcagatga atagcctgag agccgaggac accgccgtct actactgcgc tagagactat 300 agaaagggcc tgtacgctat ggactactgg ggtcaaggca ctaccgtgac cgtgtcttca 360 gctagcacta agggcccgtc cgtgttcccc ctggcacctt gtagccggag cactagcgaa 420 tccaccgctg ccctcggctg cctggtcaag gattacttcc cggagcccgt gaccgtgtcc 480 tggaacagcg gagccctgac ctccggagtg cacaccttcc ccgctgtgct gcagagctcc 540 gggctgtact cgctgtcgtc ggtggtcacg gtgccttcat ctagcctggg taccaagacc 600 tacacttgca acgtggacca caagccttcc aacactaagg tggacaagcg cgtcgaatcg 660 aagtacggcc caccgtgccc gccttgtccc gcgccggagt tcctcggcgg tccctcggtc 720 tttctgttcc caccgaagcc caaggacact ttgatgattt cccgcacccc tgaagtgaca 780 tgcgtggtcg tggacgtgtc acaggaagat ccggaggtgc agttcaattg gtacgtggat 840 ggcgtcgagg tgcacaacgc caaaaccaag ccgagggagg agcagttcaa ctccacttac 900 cgcgtcgtgt ccgtgctgac ggtgctgcat caggactggc tgaacgggaa ggagtacaag 960 tgcaaagtgt ccaacaaggg acttcctagc tcaatcgaaa agaccatctc gaaagccaag 1020 ggacagcccc gggaacccca agtgtatacc ctgccaccga gccaggaaga aatgactaag 1080 aaccaagtct cattgacttg ccttgtgaag ggcttctacc catcggatat cgccgtggaa 1140 tgggagtcca acggccagcc ggaaaacaac tacaagacca cccctccggt gctggactca 1200 gacggatcct tcttcctcta ctcgcggctg accgtggata agagcagatg gcaggaggga 1260 aatgtgttca gctgttctgt gatgcatgaa gccctgcaca accactacac tcagaagtcc 1320 ctgtccctct ccctggga 1338 <210> 616 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 616 Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala             20 25 30 Val Ala Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile         35 40 45 Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Glu Ala 65 70 75 80 Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu                 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             100 105 <210> 617 <211> 321 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 617 gctattcagc tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact 60 atcacctgta aagcctctca ggacgtgggc accgccgtgg cctggtatct gcagaagcct 120 ggtcaatcac ctcagctgct gatctactgg gcctctacta gacacaccgg cgtgccctct 180 aggtttagcg gtagcggtag tggcaccgac ttcaccttca ctatctcttc actggaagcc 240 gaggacgccg ctacctacta ctgtcagcag tataatagct accccctgac cttcggtcaa 300 ggcactaagg tcgagattaa g 321 <210> 618 <211> 214 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 618 Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala             20 25 30 Val Ala Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile         35 40 45 Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Glu Ala 65 70 75 80 Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu                 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala             100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly         115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala     130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser                 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr             180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser         195 200 205 Phe Asn Arg Gly Glu Cys     210 <210> 619 <211> 642 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 619 gctattcagc tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact 60 atcacctgta aagcctctca ggacgtgggc accgccgtgg cctggtatct gcagaagcct 120 ggtcaatcac ctcagctgct gatctactgg gcctctacta gacacaccgg cgtgccctct 180 aggtttagcg gtagcggtag tggcaccgac ttcaccttca ctatctcttc actggaagcc 240 gaggacgccg ctacctacta ctgtcagcag tataatagct accccctgac cttcggtcaa 300 ggcactaagg tcgagattaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc 360 agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420 ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540 ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 600 ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642 <210> 620 <211> 120 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 620 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Ser Tyr             20 25 30 Trp Met Tyr Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met         35 40 45 Gly Arg Ile Asp Pro Asn Ser Gly Ser Thr Lys Tyr Asn Glu Lys Phe     50 55 60 Lys Asn Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Asp Tyr Arg Lys Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln             100 105 110 Gly Thr Thr Val Thr Val Ser Ser         115 120 <210> 621 <211> 360 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 621 gaagtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctac cgtgaagatt 60 agctgtaaag tctcaggcta caccttcact agctactgga tgtactgggt ccgacaggct 120 accggtcaag gcctggagtg gatgggtaga atcgacccta atagcggctc tactaagtat 180 aacgagaagt ttaagaatag agtgactatc accgccgata agtctactag caccgcctat 240 atggaactgt ctagcctgag atcagaggac accgccgtct actactgcgc tagagactat 300 agaaagggcc tgtacgctat ggactactgg ggtcaaggca ctaccgtgac cgtgtcttca 360 <210> 622 <211> 446 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 622 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Ser Tyr             20 25 30 Trp Met Tyr Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met         35 40 45 Gly Arg Ile Asp Pro Asn Ser Gly Ser Thr Lys Tyr Asn Glu Lys Phe     50 55 60 Lys Asn Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Asp Tyr Arg Lys Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln             100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val         115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala     130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val                 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro             180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys         195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro     210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr                 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu             260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys         275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser     290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile                 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro             340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu         355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn     370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg                 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu             420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly         435 440 445 <210> 623 <211> 1338 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 623 gaagtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctac cgtgaagatt 60 agctgtaaag tctcaggcta caccttcact agctactgga tgtactgggt ccgacaggct 120 accggtcaag gcctggagtg gatgggtaga atcgacccta atagcggctc tactaagtat 180 aacgagaagt ttaagaatag agtgactatc accgccgata agtctactag caccgcctat 240 atggaactgt ctagcctgag atcagaggac accgccgtct actactgcgc tagagactat 300 agaaagggcc tgtacgctat ggactactgg ggtcaaggca ctaccgtgac cgtgtcttca 360 gctagcacta agggcccgtc cgtgttcccc ctggcacctt gtagccggag cactagcgaa 420 tccaccgctg ccctcggctg cctggtcaag gattacttcc cggagcccgt gaccgtgtcc 480 tggaacagcg gagccctgac ctccggagtg cacaccttcc ccgctgtgct gcagagctcc 540 gggctgtact cgctgtcgtc ggtggtcacg gtgccttcat ctagcctggg taccaagacc 600 tacacttgca acgtggacca caagccttcc aacactaagg tggacaagcg cgtcgaatcg 660 aagtacggcc caccgtgccc gccttgtccc gcgccggagt tcctcggcgg tccctcggtc 720 tttctgttcc caccgaagcc caaggacact ttgatgattt cccgcacccc tgaagtgaca 780 tgcgtggtcg tggacgtgtc acaggaagat ccggaggtgc agttcaattg gtacgtggat 840 ggcgtcgagg tgcacaacgc caaaaccaag ccgagggagg agcagttcaa ctccacttac 900 cgcgtcgtgt ccgtgctgac ggtgctgcat caggactggc tgaacgggaa ggagtacaag 960 tgcaaagtgt ccaacaaggg acttcctagc tcaatcgaaa agaccatctc gaaagccaag 1020 ggacagcccc gggaacccca agtgtatacc ctgccaccga gccaggaaga aatgactaag 1080 aaccaagtct cattgacttg ccttgtgaag ggcttctacc catcggatat cgccgtggaa 1140 tgggagtcca acggccagcc ggaaaacaac tacaagacca cccctccggt gctggactca 1200 gacggatcct tcttcctcta ctcgcggctg accgtggata agagcagatg gcaggaggga 1260 aatgtgttca gctgttctgt gatgcatgaa gccctgcaca accactacac tcagaagtcc 1320 ctgtccctct ccctggga 1338 <210> 624 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 624 Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Ala             20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile         35 40 45 Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu                 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             100 105 <210> 625 <211> 321 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 625 gacgtcgtga tgactcagtc acccctgagc ctgcccgtga ccctggggca gcccgcctct 60 attagctgta aagcctctca ggacgtgggc accgccgtgg cctggtatca gcagaagcca 120 gggcaagccc ctagactgct gatctactgg gcctctacta gacacaccgg cgtgccctct 180 aggtttagcg gtagcggtag tggcaccgag ttcaccctga ctatctcttc actgcagccc 240 gacgacttcg ctacctacta ctgtcagcag tataatagct accccctgac cttcggtcaa 300 ggcactaagg tcgagattaa g 321 <210> 626 <211> 214 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 626 Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Ala             20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile         35 40 45 Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly     50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu                 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala             100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly         115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala     130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser                 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr             180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser         195 200 205 Phe Asn Arg Gly Glu Cys     210 <210> 627 <211> 642 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 627 gacgtcgtga tgactcagtc acccctgagc ctgcccgtga ccctggggca gcccgcctct 60 attagctgta aagcctctca ggacgtgggc accgccgtgg cctggtatca gcagaagcca 120 gggcaagccc ctagactgct gatctactgg gcctctacta gacacaccgg cgtgccctct 180 aggtttagcg gtagcggtag tggcaccgag ttcaccctga ctatctcttc actgcagccc 240 gacgacttcg ctacctacta ctgtcagcag tataatagct accccctgac cttcggtcaa 300 ggcactaagg tcgagattaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc 360 agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420 ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540 ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 600 ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642 <210> 628 <211> 15 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 628 agctactgga tgtac 15 <210> 629 <211> 51 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 629 agaatcgacc ctaatagcgg ctctactaag tataacgaga agtttaagaa t 51 <210> 630 <211> 33 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 630 gactatagaa agggcctgta cgctatggac tac 33 <210> 631 <211> 21 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 631 ggctacacct tcactagcta c 21 <210> 632 <211> 18 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 632 gaccctaata gcggctct 18 <210> 633 <211> 33 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 633 aaagcctctc aggacgtggg caccgccgtg gcc 33 <210> 634 <211> 21 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 634 tgggcctcta ctagacacac c 21 <210> 635 <211> 27 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 635 cagcagtata atagctaccc cctgacc 27 <210> 636 <211> 21 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 636 tctcaggacg tgggcaccgc c 21 <210> 637 <211> 9 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 637 tgggcctct 9 <210> 638 <211> 18 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 638 tataatagct accccctg 18 <210> 639 <211> 448 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 639 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser             20 25 30 Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr             100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro         115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly     130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln                 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser             180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser         195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr     210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg                 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro             260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala         275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val     290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr                 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu             340 345 350 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys         355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser     370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser                 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala             420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys         435 440 445 <210> 640 <211> 214 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 640 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala             20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile         35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly     50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala                 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala             100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly         115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala     130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser                 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr             180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser         195 200 205 Phe Asn Arg Gly Glu Cys     210 <210> 641 <211> 450 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 641 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr             20 25 30 Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln             100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val         115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala     130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val                 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro             180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys         195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp     210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile                 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu             260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His         275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg     290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu                 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr             340 345 350 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu         355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp     370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp                 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His             420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro         435 440 445 Gly Lys     450 <210> 642 <211> 216 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 642 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr             20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu         35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe     50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser                 85 90 95 Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Gln             100 105 110 Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu         115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr     130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr                 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His             180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys         195 200 205 Thr Val Ala Pro Thr Glu Cys Ser     210 215 <210> 643 <211> 451 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 643 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr             20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr Trp Gly             100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser         115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala     130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala                 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val             180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His         195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys     210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met                 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His             260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val         275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr     290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile                 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val             340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser         355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu     370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val                 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met             420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser         435 440 445 Pro Gly Lys     450 <210> 644 <211> 215 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 644 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Arg Val Ser Ser Ser             20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu         35 40 45 Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser     50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Leu Pro                 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala             100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser         115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu     130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu                 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val             180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys         195 200 205 Ser Phe Asn Arg Gly Glu Cys     210 215 <210> 645 <211> 123 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 645 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Gly Asp Thr Phe Ser Thr Tyr             20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met         35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Lys Ala His Tyr Ala Gln Lys Phe     50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys                 85 90 95 Ala Arg Lys Phe His Phe Val Ser Gly Ser Pro Phe Gly Met Asp Val             100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser         115 120 <210> 646 <211> 106 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 646 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr             20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile         35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly     50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Thr                 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             100 105 <210> 647 <211> 10 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 647 Gly Tyr Thr Phe Thr Ser Tyr Trp Met Tyr 1 5 10 <210> 648 <400> 648 000 <210> 649 <400> 649 000 <210> 650 <400> 650 000 <210> 651 <400> 651 000 <210> 652 <400> 652 000 <210> 653 <400> 653 000 <210> 654 <400> 654 000 <210> 655 <400> 655 000 <210> 656 <400> 656 000 <210> 657 <400> 657 000 <210> 658 <400> 658 000 <210> 659 <400> 659 000 <210> 660 <400> 660 000 <210> 661 <400> 661 000 <210> 662 <400> 662 000 <210> 663 <400> 663 000 <210> 664 <400> 664 000 <210> 665 <400> 665 000 <210> 666 <400> 666 000 <210> 667 <400> 667 000 <210> 668 <400> 668 000 <210> 669 <400> 669 000 <210> 670 <400> 670 000 <210> 671 <400> 671 000 <210> 672 <400> 672 000 <210> 673 <400> 673 000 <210> 674 <400> 674 000 <210> 675 <400> 675 000 <210> 676 <400> 676 000 <210> 677 <400> 677 000 <210> 678 <400> 678 000 <210> 679 <400> 679 000 <210> 680 <400> 680 000 <210> 681 <400> 681 000 <210> 682 <400> 682 000 <210> 683 <400> 683 000 <210> 684 <400> 684 000 <210> 685 <400> 685 000 <210> 686 <400> 686 000 <210> 687 <400> 687 000 <210> 688 <400> 688 000 <210> 689 <400> 689 000 <210> 690 <400> 690 000 <210> 691 <400> 691 000 <210> 692 <400> 692 000 <210> 693 <400> 693 000 <210> 694 <400> 694 000 <210> 695 <400> 695 000 <210> 696 <400> 696 000 <210> 697 <400> 697 000 <210> 698 <400> 698 000 <210> 699 <400> 699 000 <210> 700 <400> 700 000 <210> 701 <211> 5 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 701 Asn Tyr Gly Met Asn 1 5 <210> 702 <211> 17 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 702 Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe Lys 1 5 10 15 Gly      <210> 703 <211> 16 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 703 Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Ala Glu Ala Met Asp Tyr 1 5 10 15 <210> 704 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 704 Gly Phe Thr Leu Thr Asn Tyr 1 5 <210> 705 <211> 6 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 705 Asn Thr Asp Thr Gly Glu 1 5 <210> 706 <211> 125 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 706 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Leu Thr Asn Tyr             20 25 30 Gly Met Asn Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Ile         35 40 45 Gly Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe     50 55 60 Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Ala Glu Ala Met             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser         115 120 125 <210> 707 <211> 375 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 707 caagtgcagc tggtgcagtc gggagccgaa gtgaagaagc ctggagcctc ggtgaaggtg 60 tcgtgcaagg catccggatt caccctcacc aattacggga tgaactgggt cagacaggcc 120 cggggtcaac ggctggagtg gatcggatgg attaacaccg acaccgggga gcctacctac 180 gcggacgatt tcaagggacg gttcgtgttc tccctcgaca cctccgtgtc caccgcctac 240 ctccaaatct cctcactgaa agcggaggac accgccgtgt actattgcgc gaggaacccg 300 ccctactact acggaaccaa caacgccgaa gccatggact actggggcca gggcaccact 360 gtgactgtgt ccagc 375 <210> 708 <211> 375 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 708 caggtgcagc tggtgcagtc tggcgccgaa gtgaagaaac ctggcgcctc cgtgaaggtg 60 tcctgcaagg cctctggctt caccctgacc aactacggca tgaactgggt gcgacaggcc 120 aggggccagc ggctggaatg gatcggctgg atcaacaccg acaccggcga gcctacctac 180 gccgacgact tcaagggcag attcgtgttc tccctggaca cctccgtgtc caccgcctac 240 ctgcagatct ccagcctgaa ggccgaggat accgccgtgt actactgcgc ccggaacccc 300 ccttactact acggcaccaa caacgccgag gccatggact attggggcca gggcaccacc 360 gtgaccgtgt cctct 375 <210> 709 <211> 451 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 709 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Leu Thr Asn Tyr             20 25 30 Gly Met Asn Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Ile         35 40 45 Gly Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe     50 55 60 Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Ala Glu Ala Met             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr         115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser     130 135 140 Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His                 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser             180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys         195 200 205 Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu     210 215 220 Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu 225 230 235 240 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu                 245 250 255 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser             260 265 270 Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu         275 280 285 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr     290 295 300 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 305 310 315 320 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser                 325 330 335 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln             340 345 350 Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val         355 360 365 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val     370 375 380 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 385 390 395 400 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr                 405 410 415 Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val             420 425 430 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu         435 440 445 Ser Leu Gly     450 <210> 710 <211> 11 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 710 Ser Ser Ser Gln Asp Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 711 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 711 Tyr Thr Ser Thr Leu His Leu 1 5 <210> 712 <211> 9 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 712 Gln Gln Tyr Tyr Asn Leu Pro Trp Thr 1 5 <210> 713 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 713 Ser Gln Asp Ile Ser Asn Tyr 1 5 <210> 714 <211> 3 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 714 Tyr Thr Ser One <210> 715 <211> 6 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 715 Tyr Tyr Asn Leu Pro Trp 1 5 <210> 716 <211> 1353 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 716 caagtgcagc tggtgcagtc gggagccgaa gtgaagaagc ctggagcctc ggtgaaggtg 60 tcgtgcaagg catccggatt caccctcacc aattacggga tgaactgggt cagacaggcc 120 cggggtcaac ggctggagtg gatcggatgg attaacaccg acaccgggga gcctacctac 180 gcggacgatt tcaagggacg gttcgtgttc tccctcgaca cctccgtgtc caccgcctac 240 ctccaaatct cctcactgaa agcggaggac accgccgtgt actattgcgc gaggaacccg 300 ccctactact acggaaccaa caacgccgaa gccatggact actggggcca gggcaccact 360 gtgactgtgt ccagcgcgtc cactaagggc ccgtccgtgt tccccctggc accttgtagc 420 cggagcacta gcgaatccac cgctgccctc ggctgcctgg tcaaggatta cttcccggag 480 cccgtgaccg tgtcctggaa cagcggagcc ctgacctccg gagtgcacac cttccccgct 540 gtgctgcaga gctccgggct gtactcgctg tcgtcggtgg tcacggtgcc ttcatctagc 600 ctgggtacca agacctacac ttgcaacgtg gaccacaagc cttccaacac taaggtggac 660 aagcgcgtcg aatcgaagta cggcccaccg tgcccgcctt gtcccgcgcc ggagttcctc 720 ggcggtccct cggtctttct gttcccaccg aagcccaagg acactttgat gatttcccgc 780 acccctgaag tgacatgcgt ggtcgtggac gtgtcacagg aagatccgga ggtgcagttc 840 aattggtacg tggatggcgt cgaggtgcac aacgccaaaa ccaagccgag ggaggagcag 900 ttcaactcca cttaccgcgt cgtgtccgtg ctgacggtgc tgcatcagga ctggctgaac 960 gggaaggagt acaagtgcaa agtgtccaac aagggacttc ctagctcaat cgaaaagacc 1020 atctcgaaag ccaagggaca gccccgggaa ccccaagtgt ataccctgcc accgagccag 1080 gaagaaatga ctaagaacca agtctcattg acttgccttg tgaagggctt ctacccatcg 1140 gatatcgccg tggaatggga gtccaacggc cagccggaaa acaactacaa gaccacccct 1200 ccggtgctgg actcagacgg atccttcttc ctctactcgc ggctgaccgt ggataagagc 1260 agatggcagg agggaaatgt gttcagctgt tctgtgatgc atgaagccct gcacaaccac 1320 tacactcaga agtccctgtc cctctccctg gga 1353 <210> 717 <211> 1353 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 717 caggtgcagc tggtgcagtc tggcgccgaa gtgaagaaac ctggcgcctc cgtgaaggtg 60 tcctgcaagg cctctggctt caccctgacc aactacggca tgaactgggt gcgacaggcc 120 aggggccagc ggctggaatg gatcggctgg atcaacaccg acaccggcga gcctacctac 180 gccgacgact tcaagggcag attcgtgttc tccctggaca cctccgtgtc caccgcctac 240 ctgcagatct ccagcctgaa ggccgaggat accgccgtgt actactgcgc ccggaacccc 300 ccttactact acggcaccaa caacgccgag gccatggact attggggcca gggcaccacc 360 gtgaccgtgt cctctgcttc taccaagggg cccagcgtgt tccccctggc cccctgctcc 420 agaagcacca gcgagagcac agccgccctg ggctgcctgg tgaaggacta cttccccgag 480 cccgtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcacca agacctacac ctgtaacgtg gaccacaagc ccagcaacac caaggtggac 660 aagagggtgg agagcaagta cggcccaccc tgccccccct gcccagcccc cgagttcctg 720 ggcggaccca gcgtgttcct gttccccccc aagcccaagg acaccctgat gatcagcaga 780 acccccgagg tgacctgtgt ggtggtggac gtgtcccagg aggacccccc ggtccagttc 840 aactggtacg tggacggcgt ggaggtgcac aacgccaaga ccaagcccag agaggagcag 900 tttaacagca cctaccgggt ggtgtccgtg ctgaccgtgc tgcaccagga ctggctgaac 960 ggcaaagagt acaagtgtaa ggtctccaac aagggcctgc caagcagcat cgaaaagacc 1020 atcagcaagg ccaagggcca gcctagagag ccccaggtct acaccctgcc acccagccaa 1080 gaggagatga ccaagaacca ggtgtccctg acctgtctgg tgaagggctt ctacccaagc 1140 gacatcgccg tggagtggga gagcaacggc cagcccgaga acaactacaa gaccaccccc 1200 ccagtgctgg acagcgacgg cagcttcttc ctgtacagca ggctgaccgt ggacaagtcc 1260 agatggcagg agggcaacgt ctttagctgc tccgtgatgc acgaggccct gcacaaccac 1320 tacacccaga agagcctgag cctgtccctg ggc 1353 <210> 718 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 718 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ser Ser Gln Asp Ile Ser Asn Tyr             20 25 30 Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile         35 40 45 Tyr Tyr Thr Ser Thr Leu His Leu Gly Val Pro Ser Arg Phe Ser Gly     50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Asn Leu Pro Trp                 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             100 105 <210> 719 <211> 321 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 719 gatattcaga tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact 60 atcacctgta gctctagtca ggatatctct aactacctga actggtatct gcagaagccc 120 ggtcaatcac ctcagctgct gatctactac actagcaccc tgcacctggg cgtgccctct 180 aggtttagcg gtagcggtag tggcaccgag ttcaccctga ctatctctag cctgcagccc 240 gacgacttcg ctacctacta ctgtcagcag tactataacc tgccctggac cttcggtcaa 300 ggcactaagg tcgagattaa g 321 <210> 720 <211> 321 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 720 gacatccaga tgacccagtc cccctccagc ctgtctgctt ccgtgggcga cagagtgacc 60 atcacctgtt cctccagcca ggacatctcc aactacctga actggtatct gcagaagccc 120 ggccagtccc ctcagctgct gatctactac acctccaccc tgcacctggg cgtgccctcc 180 agattttccg gctctggctc tggcaccgag tttaccctga ccatcagctc cctgcagccc 240 gacgacttcg ccacctacta ctgccagcag tactacaacc tgccctggac cttcggccag 300 ggcaccaagg tggaaatcaa g 321 <210> 721 <211> 214 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 721 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ser Ser Gln Asp Ile Ser Asn Tyr             20 25 30 Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile         35 40 45 Tyr Tyr Thr Ser Thr Leu His Leu Gly Val Pro Ser Arg Phe Ser Gly     50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Asn Leu Pro Trp                 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala             100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly         115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala     130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser                 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr             180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser         195 200 205 Phe Asn Arg Gly Glu Cys     210 <210> 722 <211> 642 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 722 gatattcaga tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact 60 atcacctgta gctctagtca ggatatctct aactacctga actggtatct gcagaagccc 120 ggtcaatcac ctcagctgct gatctactac actagcaccc tgcacctggg cgtgccctct 180 aggtttagcg gtagcggtag tggcaccgag ttcaccctga ctatctctag cctgcagccc 240 gacgacttcg ctacctacta ctgtcagcag tactataacc tgccctggac cttcggtcaa 300 ggcactaagg tcgagattaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc 360 agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420 ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540 ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 600 ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642 <210> 723 <211> 642 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 723 gacatccaga tgacccagtc cccctccagc ctgtctgctt ccgtgggcga cagagtgacc 60 atcacctgtt cctccagcca ggacatctcc aactacctga actggtatct gcagaagccc 120 ggccagtccc ctcagctgct gatctactac acctccaccc tgcacctggg cgtgccctcc 180 agattttccg gctctggctc tggcaccgag tttaccctga ccatcagctc cctgcagccc 240 gacgacttcg ccacctacta ctgccagcag tactacaacc tgccctggac cttcggccag 300 ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttcccccca 360 agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gtctgctgaa caacttctac 420 cccagggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540 ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gtgaggtgac ccaccagggc 600 ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642 <210> 724 <211> 125 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 724 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Leu Thr Asn Tyr             20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met         35 40 45 Gly Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe     50 55 60 Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Ala Glu Ala Met             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser         115 120 125 <210> 725 <211> 375 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 725 caggtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctag tgtgaaagtc 60 agctgtaaag ctagtggctt caccctgact aactacggga tgaactgggt ccgccaggcc 120 ccaggtcaag gcctcgagtg gatgggctgg attaacaccg acaccggcga gcctacctac 180 gccgacgact ttaagggcag attcgtgttt agcctggaca ctagtgtgtc taccgcctac 240 ctgcagatct ctagcctgaa ggccgaggac accgccgtct actactgcgc tagaaacccc 300 ccctactact acggcactaa caacgccgag gctatggact actggggtca aggcactacc 360 gtgaccgtgt ctagc 375 <210> 726 <211> 375 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 726 caggtgcagc tggtgcagtc tggcgccgaa gtgaagaaac ctggcgcctc cgtgaaggtg 60 tcctgcaagg cctctggctt caccctgacc aactacggca tgaactgggt gcgacaggcc 120 cctggacagg gcctggaatg gatgggctgg atcaacaccg acaccggcga gcctacctac 180 gccgacgact tcaagggcag attcgtgttc tccctggaca cctccgtgtc caccgcctac 240 ctgcagatct ccagcctgaa ggccgaggat accgccgtgt actactgcgc ccggaacccc 300 ccttactact acggcaccaa caacgccgag gccatggact attggggcca gggcaccacc 360 gtgaccgtgt cctct 375 <210> 727 <211> 451 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 727 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Leu Thr Asn Tyr             20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met         35 40 45 Gly Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe     50 55 60 Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Ala Glu Ala Met             100 105 110 Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr         115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser     130 135 140 Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His                 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser             180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys         195 200 205 Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu     210 215 220 Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu 225 230 235 240 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu                 245 250 255 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser             260 265 270 Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu         275 280 285 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr     290 295 300 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 305 310 315 320 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser                 325 330 335 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln             340 345 350 Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val         355 360 365 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val     370 375 380 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 385 390 395 400 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr                 405 410 415 Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val             420 425 430 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu         435 440 445 Ser Leu Gly     450 <210> 728 <211> 1353 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 728 caggtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctag tgtgaaagtc 60 agctgtaaag ctagtggctt caccctgact aactacggga tgaactgggt ccgccaggcc 120 ccaggtcaag gcctcgagtg gatgggctgg attaacaccg acaccggcga gcctacctac 180 gccgacgact ttaagggcag attcgtgttt agcctggaca ctagtgtgtc taccgcctac 240 ctgcagatct ctagcctgaa ggccgaggac accgccgtct actactgcgc tagaaacccc 300 ccctactact acggcactaa caacgccgag gctatggact actggggtca aggcactacc 360 gtgaccgtgt ctagcgctag cactaagggc ccgtccgtgt tccccctggc accttgtagc 420 cggagcacta gcgaatccac cgctgccctc ggctgcctgg tcaaggatta cttcccggag 480 cccgtgaccg tgtcctggaa cagcggagcc ctgacctccg gagtgcacac cttccccgct 540 gtgctgcaga gctccgggct gtactcgctg tcgtcggtgg tcacggtgcc ttcatctagc 600 ctgggtacca agacctacac ttgcaacgtg gaccacaagc cttccaacac taaggtggac 660 aagcgcgtcg aatcgaagta cggcccaccg tgcccgcctt gtcccgcgcc ggagttcctc 720 ggcggtccct cggtctttct gttcccaccg aagcccaagg acactttgat gatttcccgc 780 acccctgaag tgacatgcgt ggtcgtggac gtgtcacagg aagatccgga ggtgcagttc 840 aattggtacg tggatggcgt cgaggtgcac aacgccaaaa ccaagccgag ggaggagcag 900 ttcaactcca cttaccgcgt cgtgtccgtg ctgacggtgc tgcatcagga ctggctgaac 960 gggaaggagt acaagtgcaa agtgtccaac aagggacttc ctagctcaat cgaaaagacc 1020 atctcgaaag ccaagggaca gccccgggaa ccccaagtgt ataccctgcc accgagccag 1080 gaagaaatga ctaagaacca agtctcattg acttgccttg tgaagggctt ctacccatcg 1140 gatatcgccg tggaatggga gtccaacggc cagccggaaa acaactacaa gaccacccct 1200 ccggtgctgg actcagacgg atccttcttc ctctactcgc ggctgaccgt ggataagagc 1260 agatggcagg agggaaatgt gttcagctgt tctgtgatgc atgaagccct gcacaaccac 1320 tacactcaga agtccctgtc cctctccctg gga 1353 <210> 729 <211> 1353 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 729 caggtgcagc tggtgcagtc tggcgccgaa gtgaagaaac ctggcgcctc cgtgaaggtg 60 tcctgcaagg cctctggctt caccctgacc aactacggca tgaactgggt gcgacaggcc 120 cctggacagg gcctggaatg gatgggctgg atcaacaccg acaccggcga gcctacctac 180 gccgacgact tcaagggcag attcgtgttc tccctggaca cctccgtgtc caccgcctac 240 ctgcagatct ccagcctgaa ggccgaggat accgccgtgt actactgcgc ccggaacccc 300 ccttactact acggcaccaa caacgccgag gccatggact attggggcca gggcaccacc 360 gtgaccgtgt cctctgcttc taccaagggg cccagcgtgt tccccctggc cccctgctcc 420 agaagcacca gcgagagcac agccgccctg ggctgcctgg tgaaggacta cttccccgag 480 cccgtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540 gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600 ctgggcacca agacctacac ctgtaacgtg gaccacaagc ccagcaacac caaggtggac 660 aagagggtgg agagcaagta cggcccaccc tgccccccct gcccagcccc cgagttcctg 720 ggcggaccca gcgtgttcct gttccccccc aagcccaagg acaccctgat gatcagcaga 780 acccccgagg tgacctgtgt ggtggtggac gtgtcccagg aggacccccc ggtccagttc 840 aactggtacg tggacggcgt ggaggtgcac aacgccaaga ccaagcccag agaggagcag 900 tttaacagca cctaccgggt ggtgtccgtg ctgaccgtgc tgcaccagga ctggctgaac 960 ggcaaagagt acaagtgtaa ggtctccaac aagggcctgc caagcagcat cgaaaagacc 1020 atcagcaagg ccaagggcca gcctagagag ccccaggtct acaccctgcc acccagccaa 1080 gaggagatga ccaagaacca ggtgtccctg acctgtctgg tgaagggctt ctacccaagc 1140 gacatcgccg tggagtggga gagcaacggc cagcccgaga acaactacaa gaccaccccc 1200 ccagtgctgg acagcgacgg cagcttcttc ctgtacagca ggctgaccgt ggacaagtcc 1260 agatggcagg agggcaacgt ctttagctgc tccgtgatgc acgaggccct gcacaaccac 1320 tacacccaga agagcctgag cctgtccctg ggc 1353 <210> 730 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 730 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ser Ser Gln Asp Ile Ser Asn Tyr             20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile         35 40 45 Tyr Tyr Thr Ser Thr Leu His Leu Gly Ile Pro Pro Arg Phe Ser Gly     50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Ile Glu Ser 65 70 75 80 Glu Asp Ala Ala Tyr Tyr Phe Cys Gln Gln Tyr Tyr Asn Leu Pro Trp                 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys             100 105 <210> 731 <211> 321 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 731 gatattcaga tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact 60 atcacctgta gctctagtca ggatatctct aactacctga actggtatca gcagaagccc 120 ggtaaagccc ctaagctgct gatctactac actagcaccc tgcacctggg aatcccccct 180 aggtttagcg gtagcggcta cggcaccgac ttcaccctga ctattaacaa tatcgagtca 240 gaggacgccg cctactactt ctgtcagcag tactataacc tgccctggac cttcggtcaa 300 ggcactaagg tcgagattaa g 321 <210> 732 <211> 321 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 732 gacatccaga tgacccagtc cccctccagc ctgtctgctt ccgtgggcga cagagtgacc 60 atcacctgtt cctccagcca ggacatctcc aactacctga actggtatca gcagaagccc 120 ggcaaggccc ccaagctgct gatctactac acctccaccc tgcacctggg catcccccct 180 agattctccg gctctggcta cggcaccgac ttcaccctga ccatcaacaa catcgagtcc 240 gaggacgccg cctactactt ctgccagcag tactacaacc tgccctggac cttcggccag 300 ggcaccaagg tggaaatcaa g 321 <210> 733 <211> 214 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 733 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ser Ser Gln Asp Ile Ser Asn Tyr             20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile         35 40 45 Tyr Tyr Thr Ser Thr Leu His Leu Gly Ile Pro Pro Arg Phe Ser Gly     50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Ile Glu Ser 65 70 75 80 Glu Asp Ala Ala Tyr Tyr Phe Cys Gln Gln Tyr Tyr Asn Leu Pro Trp                 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala             100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly         115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala     130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser                 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr             180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser         195 200 205 Phe Asn Arg Gly Glu Cys     210 <210> 734 <211> 642 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 734 gatattcaga tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact 60 atcacctgta gctctagtca ggatatctct aactacctga actggtatca gcagaagccc 120 ggtaaagccc ctaagctgct gatctactac actagcaccc tgcacctggg aatcccccct 180 aggtttagcg gtagcggcta cggcaccgac ttcaccctga ctattaacaa tatcgagtca 240 gaggacgccg cctactactt ctgtcagcag tactataacc tgccctggac cttcggtcaa 300 ggcactaagg tcgagattaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc 360 agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420 ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540 ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 600 ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642 <210> 735 <211> 642 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 735 gacatccaga tgacccagtc cccctccagc ctgtctgctt ccgtgggcga cagagtgacc 60 atcacctgtt cctccagcca ggacatctcc aactacctga actggtatca gcagaagccc 120 ggcaaggccc ccaagctgct gatctactac acctccaccc tgcacctggg catcccccct 180 agattctccg gctctggcta cggcaccgac ttcaccctga ccatcaacaa catcgagtcc 240 gaggacgccg cctactactt ctgccagcag tactacaacc tgccctggac cttcggccag 300 ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttcccccca 360 agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gtctgctgaa caacttctac 420 cccagggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540 ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gtgaggtgac ccaccagggc 600 ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642 <210> 736 <211> 15 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 736 aattacggga tgaac 15 <210> 737 <211> 15 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 737 aactacggca tgaac 15 <210> 738 <211> 51 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 738 tggattaaca ccgacaccgg ggagcctacc tacgcggacg atttcaaggg a 51 <210> 739 <211> 51 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 739 tggatcaaca ccgacaccgg cgagcctacc tacgccgacg acttcaaggg c 51 <210> 740 <211> 48 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 740 aacccgccct actactacgg aaccaacaac gccgaagcca tggactac 48 <210> 741 <211> 48 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 741 aacccccctt actactacgg caccaacaac gccgaggcca tggactat 48 <210> 742 <211> 21 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 742 ggattcaccc tcaccaatta c 21 <210> 743 <211> 21 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 743 ggcttcaccc tgaccaacta c 21 <210> 744 <211> 18 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 744 aacaccgaca ccggggag 18 <210> 745 <211> 18 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 745 aacaccgaca ccggcgag 18 <210> 746 <211> 33 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 746 agctctagtc aggatatctc taactacctg aac 33 <210> 747 <211> 33 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 747 tcctccagcc aggacatctc caactacctg aac 33 <210> 748 <211> 21 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 748 tacactagca ccctgcacct g 21 <210> 749 <211> 21 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 749 tacacctcca ccctgcacct g 21 <210> 750 <211> 27 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 750 cagcagtact ataacctgcc ctggacc 27 <210> 751 <211> 27 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 751 cagcagtact acaacctgcc ctggacc 27 <210> 752 <211> 21 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 752 agtcaggata tctctaacta c 21 <210> 753 <211> 21 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 753 agccaggaca tctccaacta c 21 <210> 754 <211> 9 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 754 tacactagc 9 <210> 755 <211> 9 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 755 tacacctcc 9 <210> 756 <211> 18 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 756 tactataacc tgccctgg 18 <210> 757 <211> 18 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 757 tactacaacc tgccctgg 18 <210> 758 <211> 15 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 758 aactacggga tgaac 15 <210> 759 <211> 51 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 759 tggattaaca ccgacaccgg cgagcctacc tacgccgacg actttaaggg c 51 <210> 760 <211> 48 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 760 aaccccccct actactacgg cactaacaac gccgaggcta tggactac 48 <210> 761 <211> 21 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       oligonucleotide " <400> 761 ggcttcaccc tgactaacta c 21 <210> 762 <211> 447 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 762 Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Asp Tyr             20 25 30 Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile         35 40 45 Gly Glu Ile Asn His Arg Gly Ser Thr Asn Ser Asn Pro Ser Leu Lys     50 55 60 Ser Arg Val Thr Leu Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala                 85 90 95 Phe Gly Tyr Ser Asp Tyr Glu Tyr Asn Trp Phe Asp Pro Trp Gly Gln             100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val         115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala     130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val                 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro             180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys         195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro     210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr                 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu             260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys         275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser     290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile                 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro             340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu         355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn     370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg                 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu             420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys         435 440 445 <210> 763 <211> 214 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 763 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr             20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile         35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly     50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu                 85 90 95 Thr Phe Gly Gln Gly Thr Asn Leu Glu Ile Lys Arg Thr Val Ala Ala             100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly         115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala     130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser                 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr             180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser         195 200 205 Phe Asn Arg Gly Glu Cys     210 <210> 764 <211> 446 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 764 Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ala Tyr             20 25 30 Gly Val Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu         35 40 45 Gly Met Ile Trp Asp Asp Gly Ser Thr Asp Tyr Asn Ser Ala Leu Lys     50 55 60 Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu 65 70 75 80 Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Arg Tyr Tyr Cys Ala                 85 90 95 Arg Glu Gly Asp Val Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu             100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala         115 120 125 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu     130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser                 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu             180 185 190 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr         195 200 205 Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr     210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro                 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val             260 265 270 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr         275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val     290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser                 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro             340 345 350 Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val         355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly     370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp                 405 410 415 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His             420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys         435 440 445 <210> 765 <211> 220 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 765 Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly 1 5 10 15 Gln Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Gly             20 25 30 Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln         35 40 45 Ser Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Asp Ser Gly Val     50 55 60 Pro Asp Arg Phe Ile Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Asp Tyr Phe Cys Leu Gln                 85 90 95 His Phe Gly Thr Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile             100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp         115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn     130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp                 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr             180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser         195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys     210 215 220 <210> 766 <211> 10 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 766 Gly Phe Thr Leu Thr Asn Tyr Gly Met Asn 1 5 10 <210> 767 <400> 767 000 <210> 768 <400> 768 000 <210> 769 <400> 769 000 <210> 770 <400> 770 000 <210> 771 <400> 771 000 <210> 772 <400> 772 000 <210> 773 <400> 773 000 <210> 774 <400> 774 000 <210> 775 <400> 775 000 <210> 776 <400> 776 000 <210> 777 <400> 777 000 <210> 778 <400> 778 000 <210> 779 <400> 779 000 <210> 780 <400> 780 000 <210> 781 <400> 781 000 <210> 782 <400> 782 000 <210> 783 <400> 783 000 <210> 784 <400> 784 000 <210> 785 <400> 785 000 <210> 786 <400> 786 000 <210> 787 <400> 787 000 <210> 788 <400> 788 000 <210> 789 <400> 789 000 <210> 790 <400> 790 000 <210> 791 <400> 791 000 <210> 792 <400> 792 000 <210> 793 <400> 793 000 <210> 794 <400> 794 000 <210> 795 <400> 795 000 <210> 796 <400> 796 000 <210> 797 <400> 797 000 <210> 798 <400> 798 000 <210> 799 <400> 799 000 <210> 800 <400> 800 000 <210> 801 <211> 5 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 801 Ser Tyr Asn Met His 1 5 <210> 802 <211> 17 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 802 Asp Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly      <210> 803 <211> 9 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 803 Val Gly Gly Ala Phe Pro Met Asp Tyr 1 5 <210> 804 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 804 Gly Tyr Thr Phe Thr Ser Tyr 1 5 <210> 805 <211> 6 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 805 Tyr Pro Gly Asn Gly Asp 1 5 <210> 806 <211> 118 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 806 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr             20 25 30 Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met         35 40 45 Gly Asp Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe     50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Val Gly Gly Ala Phe Pro Met Asp Tyr Trp Gly Gln Gly Thr             100 105 110 Thr Val Thr Val Ser Ser         115 <210> 807 <211> 354 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 807 caggtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggctctag cgtgaaagtt 60 tcttgtaaag ctagtggcta caccttcact agctataata tgcactgggt tcgccaggcc 120 ccagggcaag gcctcgagtg gatgggcgat atctaccccg ggaacggcga cactagttat 180 aatcagaagt ttaagggtag agtcactatc accgccgata agtctactag caccgtctat 240 atggaactga gttccctgag gtctgaggac accgccgtct actactgcgc tagagtgggc 300 ggagccttcc ctatggacta ctggggtcaa ggcactaccg tgaccgtgtc tagc 354 <210> 808 <211> 444 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 808 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr             20 25 30 Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met         35 40 45 Gly Asp Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe     50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Val Gly Gly Ala Phe Pro Met Asp Tyr Trp Gly Gln Gly Thr             100 105 110 Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro         115 120 125 Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly     130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln                 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser             180 185 190 Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser         195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys     210 215 220 Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu                 245 250 255 Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln             260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys         275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu     290 295 300 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys                 325 330 335 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser             340 345 350 Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys         355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln     370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln                 405 410 415 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn             420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly         435 440 <210> 809 <211> 1332 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 809 caggtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggctctag cgtgaaagtt 60 tcttgtaaag ctagtggcta caccttcact agctataata tgcactgggt tcgccaggcc 120 ccagggcaag gcctcgagtg gatgggcgat atctaccccg ggaacggcga cactagttat 180 aatcagaagt ttaagggtag agtcactatc accgccgata agtctactag caccgtctat 240 atggaactga gttccctgag gtctgaggac accgccgtct actactgcgc tagagtgggc 300 ggagccttcc ctatggacta ctggggtcaa ggcactaccg tgaccgtgtc tagcgctagc 360 actaagggcc cgtccgtgtt ccccctggca ccttgtagcc ggagcactag cgaatccacc 420 gctgccctcg gctgcctggt caaggattac ttcccggagc ccgtgaccgt gtcctggaac 480 agcggagccc tgacctccgg agtgcacacc ttccccgctg tgctgcagag ctccgggctg 540 tactcgctgt cgtcggtggt cacggtgcct tcatctagcc tgggtaccaa gacctacact 600 tgcaacgtgg accacaagcc ttccaacact aaggtggaca agcgcgtcga atcgaagtac 660 ggcccaccgt gcccgccttg tcccgcgccg gagttcctcg gcggtccctc ggtctttctg 720 ttcccaccga agcccaagga cactttgatg atttcccgca cccctgaagt gacatgcgtg 780 gtcgtggacg tgtcacagga agatccggag gtgcagttca attggtacgt ggatggcgtc 840 gaggtgcaca acgccaaaac caagccgagg gaggagcagt tcaactccac ttaccgcgtc 900 gtgtccgtgc tgacggtgct gcatcaggac tggctgaacg ggaaggagta caagtgcaaa 960 gtgtccaaca agggacttcc tagctcaatc gaaaagacca tctcgaaagc caagggacag 1020 ccccgggaac cccaagtgta taccctgcca ccgagccagg aagaaatgac taagaaccaa 1080 gtctcattga cttgccttgt gaagggcttc tacccatcgg atatcgccgt ggaatgggag 1140 tccaacggcc agccggaaaa caactacaag accacccctc cggtgctgga ctcagacgga 1200 tccttcttcc tctactcgcg gctgaccgtg gataagagca gatggcagga gggaaatgtg 1260 ttcagctgtt ctgtgatgca tgaagccctg cacaaccact acactcagaa gtccctgtcc 1320 ctctccctgg ga 1332 <210> 810 <211> 15 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 810 Arg Ala Ser Glu Ser Val Glu Tyr Tyr Gly Thr Ser Leu Met Gln 1 5 10 15 <210> 811 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 811 Ala Ala Ser Asn Val Glu Ser 1 5 <210> 812 <211> 9 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 812 Gln Gln Ser Arg Lys Asp Pro Ser Thr 1 5 <210> 813 <211> 11 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 813 Ser Glu Ser Val Glu Tyr Tyr Gly Thr Ser Leu 1 5 10 <210> 814 <211> 3 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 814 Ala Ala Ser One <210> 815 <211> 6 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 815 Ser Arg Lys Asp Pro Ser 1 5 <210> 816 <211> 111 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 816 Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr             20 25 30 Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro         35 40 45 Lys Leu Leu Ile Tyr Ala Ala Ser Asn Val Glu Ser Gly Val Pro Ser     50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Ser Arg                 85 90 95 Lys Asp Pro Ser Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys             100 105 110 <210> 817 <211> 333 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 817 gctattcagc tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact 60 atcacctgta gagctagtga atcagtcgag tactacggca ctagcctgat gcagtggtat 120 cagcagaagc ccgggaaagc ccctaagctg ctgatctacg ccgcctctaa cgtggaatca 180 ggcgtgccct ctaggtttag cggtagcggt agtggcaccg acttcaccct gactatctct 240 agcctgcagc ccgaggactt cgctacctac ttctgtcagc agtctaggaa ggaccctagc 300 accttcggcg gaggcactaa ggtcgagatt aag 333 <210> 818 <211> 218 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 818 Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr             20 25 30 Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro         35 40 45 Lys Leu Leu Ile Tyr Ala Ala Ser Asn Val Glu Ser Gly Val Pro Ser     50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Ser Arg                 85 90 95 Lys Asp Pro Ser Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg             100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln         115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr     130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr                 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys             180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro         195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys     210 215 <210> 819 <211> 654 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 819 gctattcagc tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact 60 atcacctgta gagctagtga atcagtcgag tactacggca ctagcctgat gcagtggtat 120 cagcagaagc ccgggaaagc ccctaagctg ctgatctacg ccgcctctaa cgtggaatca 180 ggcgtgccct ctaggtttag cggtagcggt agtggcaccg acttcaccct gactatctct 240 agcctgcagc ccgaggactt cgctacctac ttctgtcagc agtctaggaa ggaccctagc 300 accttcggcg gaggcactaa ggtcgagatt aagcgtacgg tggccgctcc cagcgtgttc 360 atcttccccc ccagcgacga gcagctgaag agcggcaccg ccagcgtggt gtgcctgctg 420 aacaacttct acccccggga ggccaaggtg cagtggaagg tggacaacgc cctgcagagc 480 ggcaacagcc aggagagcgt caccgagcag gacagcaagg actccaccta cagcctgagc 540 agcaccctga ccctgagcaa ggccgactac gagaagcata aggtgtacgc ctgcgaggtg 600 acccaccagg gcctgtccag ccccgtgacc aagagcttca acaggggcga gtgc 654 <210> 820 <211> 17 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 820 Asp Ile Tyr Pro Gly Gln Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly      <210> 821 <211> 6 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 821 Tyr Pro Gly Gln Gly Asp 1 5 <210> 822 <211> 118 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 822 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr             20 25 30 Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile         35 40 45 Gly Asp Ile Tyr Pro Gly Gln Gly Asp Thr Ser Tyr Asn Gln Lys Phe     50 55 60 Lys Gly Arg Ala Thr Met Thr Ala Asp Lys Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Val Gly Gly Ala Phe Pro Met Asp Tyr Trp Gly Gln Gly Thr             100 105 110 Leu Val Thr Val Ser Ser         115 <210> 823 <211> 354 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 823 caggtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctag tgtgaaagtt 60 agctgtaaag ctagtggcta tactttcact tcttataata tgcactgggt ccgccaggcc 120 ccaggtcaag gcctcgagtg gatcggcgat atctaccccg gtcaaggcga cacttcctat 180 aatcagaagt ttaagggtag agctactatg accgccgata agtctacttc taccgtctat 240 atggaactga gttccctgag gtctgaggac accgccgtct actactgcgc tagagtgggc 300 ggagccttcc caatggacta ctggggtcaa ggcaccctgg tcaccgtgtc tagc 354 <210> 824 <211> 444 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 824 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr             20 25 30 Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile         35 40 45 Gly Asp Ile Tyr Pro Gly Gln Gly Asp Thr Ser Tyr Asn Gln Lys Phe     50 55 60 Lys Gly Arg Ala Thr Met Thr Ala Asp Lys Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Val Gly Gly Ala Phe Pro Met Asp Tyr Trp Gly Gln Gly Thr             100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro         115 120 125 Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly     130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln                 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser             180 185 190 Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser         195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys     210 215 220 Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu                 245 250 255 Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln             260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys         275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu     290 295 300 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys                 325 330 335 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser             340 345 350 Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys         355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln     370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln                 405 410 415 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn             420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly         435 440 <210> 825 <211> 1332 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 825 caggtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctag tgtgaaagtt 60 agctgtaaag ctagtggcta tactttcact tcttataata tgcactgggt ccgccaggcc 120 ccaggtcaag gcctcgagtg gatcggcgat atctaccccg gtcaaggcga cacttcctat 180 aatcagaagt ttaagggtag agctactatg accgccgata agtctacttc taccgtctat 240 atggaactga gttccctgag gtctgaggac accgccgtct actactgcgc tagagtgggc 300 ggagccttcc caatggacta ctggggtcaa ggcaccctgg tcaccgtgtc tagcgctagc 360 actaagggcc cgtccgtgtt ccccctggca ccttgtagcc ggagcactag cgaatccacc 420 gctgccctcg gctgcctggt caaggattac ttcccggagc ccgtgaccgt gtcctggaac 480 agcggagccc tgacctccgg agtgcacacc ttccccgctg tgctgcagag ctccgggctg 540 tactcgctgt cgtcggtggt cacggtgcct tcatctagcc tgggtaccaa gacctacact 600 tgcaacgtgg accacaagcc ttccaacact aaggtggaca agcgcgtcga atcgaagtac 660 ggcccaccgt gcccgccttg tcccgcgccg gagttcctcg gcggtccctc ggtctttctg 720 ttcccaccga agcccaagga cactttgatg atttcccgca cccctgaagt gacatgcgtg 780 gtcgtggacg tgtcacagga agatccggag gtgcagttca attggtacgt ggatggcgtc 840 gaggtgcaca acgccaaaac caagccgagg gaggagcagt tcaactccac ttaccgcgtc 900 gtgtccgtgc tgacggtgct gcatcaggac tggctgaacg ggaaggagta caagtgcaaa 960 gtgtccaaca agggacttcc tagctcaatc gaaaagacca tctcgaaagc caagggacag 1020 ccccgggaac cccaagtgta taccctgcca ccgagccagg aagaaatgac taagaaccaa 1080 gtctcattga cttgccttgt gaagggcttc tacccatcgg atatcgccgt ggaatgggag 1140 tccaacggcc agccggaaaa caactacaag accacccctc cggtgctgga ctcagacgga 1200 tccttcttcc tctactcgcg gctgaccgtg gataagagca gatggcagga gggaaatgtg 1260 ttcagctgtt ctgtgatgca tgaagccctg cacaaccact acactcagaa gtccctgtcc 1320 ctctccctgg ga 1332 <210> 826 <211> 111 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 826 Asp Ile Val Leu Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr             20 25 30 Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro         35 40 45 Lys Leu Leu Ile Tyr Ala Ala Ser Asn Val Glu Ser Gly Val Pro Asp     50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Ser Arg                 85 90 95 Lys Asp Pro Ser Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys             100 105 110 <210> 827 <211> 333 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 827 gatatcgtcc tgactcagtc acccgatagc ctggccgtca gcctgggcga gcgggctact 60 attaactgta gagctagtga atcagtcgag tactacggca ctagcctgat gcagtggtat 120 cagcagaagc ccggtcaacc ccctaagctg ctgatctacg ccgcctctaa cgtggaatca 180 ggcgtgcccg ataggtttag cggtagcggt agtggcaccg acttcaccct gactattagt 240 agcctgcagg ccgaggacgt ggccgtctac tactgtcagc agtctaggaa ggaccctagc 300 accttcggcg gaggcactaa ggtcgagatt aag 333 <210> 828 <211> 218 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 828 Asp Ile Val Leu Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr             20 25 30 Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro         35 40 45 Lys Leu Leu Ile Tyr Ala Ala Ser Asn Val Glu Ser Gly Val Pro Asp     50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Ser Arg                 85 90 95 Lys Asp Pro Ser Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg             100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln         115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr     130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr                 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys             180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro         195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys     210 215 <210> 829 <211> 654 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 829 gatatcgtcc tgactcagtc acccgatagc ctggccgtca gcctgggcga gcgggctact 60 attaactgta gagctagtga atcagtcgag tactacggca ctagcctgat gcagtggtat 120 cagcagaagc ccggtcaacc ccctaagctg ctgatctacg ccgcctctaa cgtggaatca 180 ggcgtgcccg ataggtttag cggtagcggt agtggcaccg acttcaccct gactattagt 240 agcctgcagg ccgaggacgt ggccgtctac tactgtcagc agtctaggaa ggaccctagc 300 accttcggcg gaggcactaa ggtcgagatt aagcgtacgg tggccgctcc cagcgtgttc 360 atcttccccc ccagcgacga gcagctgaag agcggcaccg ccagcgtggt gtgcctgctg 420 aacaacttct acccccggga ggccaaggtg cagtggaagg tggacaacgc cctgcagagc 480 ggcaacagcc aggagagcgt caccgagcag gacagcaagg actccaccta cagcctgagc 540 agcaccctga ccctgagcaa ggccgactac gagaagcata aggtgtacgc ctgcgaggtg 600 acccaccagg gcctgtccag ccccgtgacc aagagcttca acaggggcga gtgc 654 <210> 830 <211> 114 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 830 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ala Ser Gly Phe Thr Phe Ser Ser             20 25 30 Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp         35 40 45 Val Ser Thr Ile Ser Gly Gly Gly Thr Tyr Thr Tyr Tyr Gln Asp Ser     50 55 60 Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 65 70 75 80 Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr                 85 90 95 Cys Ala Ser Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser             100 105 110 Ser Ala          <210> 831 <211> 108 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 831 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Arg Arg Tyr             20 25 30 Leu Asn Trp Tyr His Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile         35 40 45 Tyr Gly Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly     50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser His Ser Ala Pro Leu                 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg             100 105 <210> 832 <211> 120 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 832 Glu Val Gln Val Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Tyr Cys Val Ala Ser Gly Phe Thr Phe Ser Gly Ser             20 25 30 Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp         35 40 45 Val Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser     50 55 60 Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 65 70 75 80 Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr                 85 90 95 Cys Ala Lys Lys Tyr Tyr Val Gly Pro Ala Asp Tyr Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser Gly         115 120 <210> 833 <211> 113 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 833 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser             20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln His Lys Pro Gly Gln         35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val     50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln                 85 90 95 Tyr Tyr Ser Ser Pro Leu Thr Phe Gly Gly Gly Thr Lys Ile Glu Val             100 105 110 Lys      <210> 834 <400> 834 000 <210> 835 <400> 835 000 <210> 836 <400> 836 000 <210> 837 <400> 837 000 <210> 838 <400> 838 000 <210> 839 <400> 839 000 <210> 840 <400> 840 000 <210> 841 <400> 841 000 <210> 842 <400> 842 000 <210> 843 <400> 843 000 <210> 844 <400> 844 000 <210> 845 <400> 845 000 <210> 846 <400> 846 000 <210> 847 <400> 847 000 <210> 848 <400> 848 000 <210> 849 <400> 849 000 <210> 850 <400> 850 000 <210> 851 <400> 851 000 <210> 852 <400> 852 000 <210> 853 <400> 853 000 <210> 854 <400> 854 000 <210> 855 <400> 855 000 <210> 856 <400> 856 000 <210> 857 <400> 857 000 <210> 858 <400> 858 000 <210> 859 <400> 859 000 <210> 860 <400> 860 000 <210> 861 <400> 861 000 <210> 862 <400> 862 000 <210> 863 <400> 863 000 <210> 864 <400> 864 000 <210> 865 <400> 865 000 <210> 866 <400> 866 000 <210> 867 <400> 867 000 <210> 868 <400> 868 000 <210> 869 <400> 869 000 <210> 870 <400> 870 000 <210> 871 <400> 871 000 <210> 872 <400> 872 000 <210> 873 <400> 873 000 <210> 874 <400> 874 000 <210> 875 <400> 875 000 <210> 876 <400> 876 000 <210> 877 <400> 877 000 <210> 878 <400> 878 000 <210> 879 <400> 879 000 <210> 880 <400> 880 000 <210> 881 <400> 881 000 <210> 882 <400> 882 000 <210> 883 <400> 883 000 <210> 884 <400> 884 000 <210> 885 <400> 885 000 <210> 886 <400> 886 000 <210> 887 <400> 887 000 <210> 888 <400> 888 000 <210> 889 <400> 889 000 <210> 890 <400> 890 000 <210> 891 <400> 891 000 <210> 892 <400> 892 000 <210> 893 <400> 893 000 <210> 894 <400> 894 000 <210> 895 <400> 895 000 <210> 896 <400> 896 000 <210> 897 <400> 897 000 <210> 898 <400> 898 000 <210> 899 <400> 899 000 <210> 900 <400> 900 000 <210> 901 <211> 121 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 901 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ser Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr             20 25 30 Gly Val Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Val Ile Trp Gly Gly Gly Gly Thr Tyr Tyr Ala Ser Ser Leu Met     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala                 85 90 95 Arg His Ala Tyr Gly His Asp Gly Gly Phe Ala Met Asp Tyr Trp Gly             100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 902 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 902 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Ser Ser Asn             20 25 30 Val Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu Ile         35 40 45 Tyr Gly Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly     50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gly Gln Ser Tyr Ser Tyr Pro Phe                 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys             100 105 <210> 903 <211> 451 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 903 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ser Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr             20 25 30 Gly Val Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Gly Val Ile Trp Gly Gly Gly Gly Thr Tyr Tyr Ala Ser Ser Leu Met     50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala                 85 90 95 Arg His Ala Tyr Gly His Asp Gly Gly Phe Ala Met Asp Tyr Trp Gly             100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser         115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala     130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala                 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val             180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His         195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys     210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met                 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His             260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val         275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr     290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile                 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val             340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser         355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu     370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val                 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met             420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser         435 440 445 Pro Gly Lys     450 <210> 904 <211> 214 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 904 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Ser Ser Asn             20 25 30 Val Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu Ile         35 40 45 Tyr Gly Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly     50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gly Gln Ser Tyr Ser Tyr Pro Phe                 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala             100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly         115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala     130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser                 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr             180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser         195 200 205 Phe Asn Arg Gly Glu Cys     210 <210> 905 <211> 363 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 905 gaggtgcagc tggtggaatc tggcggcgga ctggtgcagt ccggcggctc tctgagactg 60 tcttgcgctg cctccggctt ctccctgtcc tcttacggcg tggactgggt gcgacaggcc 120 cctggcaagg gcctggaatg ggtgggagtg atctggggcg gaggcggcac ctactacgcc 180 tcttccctga tgggccggtt caccatctcc cgggacaact ccaagaacac cctgtacctg 240 cagatgaact ccctgcgggc cgaggacacc gccgtgtact actgcgccag acacgcctac 300 ggccacgacg gcggcttcgc catggattat tggggccagg gcaccctggt gacagtgtcc 360 tcc 363 <210> 906 <211> 321 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 906 gagatcgtga tgacccagtc ccccgccacc ctgtctgtgt ctcccggcga gagagccacc 60 ctgagctgca gagcctccga gtccgtgtcc tccaacgtgg cctggtatca gcagagacct 120 ggtcaggccc ctcggctgct gatctacggc gcctctaacc gggccaccgg catccctgcc 180 agattctccg gctccggcag cggcaccgac ttcaccctga ccatctcccg gctggaaccc 240 gaggacttcg ccgtgtacta ctgcggccag tcctactcat accccttcac cttcggccag 300 ggcaccaagc tggaaatcaa g 321 <210> 907 <211> 1353 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 907 gaggtgcagc tggtggaatc tggcggcgga ctggtgcagt ccggcggctc tctgagactg 60 tcttgcgctg cctccggctt ctccctgtcc tcttacggcg tggactgggt gcgacaggcc 120 cctggcaagg gcctggaatg ggtgggagtg atctggggcg gaggcggcac ctactacgcc 180 tcttccctga tgggccggtt caccatctcc cgggacaact ccaagaacac cctgtacctg 240 cagatgaact ccctgcgggc cgaggacacc gccgtgtact actgcgccag acacgcctac 300 ggccacgacg gcggcttcgc catggattat tggggccagg gcaccctggt gacagtgtcc 360 tccgctagca ccaagggccc aagtgtgttt cccctggccc ccagcagcaa gtctacttcc 420 ggcggaactg ctgccctggg ttgcctggtg aaggactact tccccgagcc cgtgacagtg 480 tcctggaact ctggggctct gacttccggc gtgcacacct tccccgccgt gctgcagagc 540 agcggcctgt acagcctgag cagcgtggtg acagtgccct ccagctctct gggaacccag 600 acctatatct gcaacgtgaa ccacaagccc agcaacacca aggtggacaa gagagtggag 660 cccaagagct gcgacaagac ccacacctgc cccccctgcc cagctccaga actgctggga 720 gggccttccg tgttcctgtt cccccccaag cccaaggaca ccctgatgat cagcaggacc 780 cccgaggtga cctgcgtggt ggtggacgtg tcccacgagg acccagaggt gaagttcaac 840 tggtacgtgg acggcgtgga ggtgcacaac gccaagacca agcccagaga ggagcagtac 900 aacagcacct acagggtggt gtccgtgctg accgtgctgc accaggactg gctgaacggc 960 aaagaataca agtgcaaagt ctccaacaag gccctgccag ccccaatcga aaagacaatc 1020 agcaaggcca agggccagcc acgggagccc caggtgtaca ccctgccccc cagccgggag 1080 gagatgacca agaaccaggt gtccctgacc tgtctggtga agggcttcta ccccagcgat 1140 atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac caccccccca 1200 gtgctggaca gcgacggcag cttcttcctg tacagcaagc tgaccgtgga caagtccagg 1260 tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac 1320 acccagaagt ccctgagcct gagccccggc aag 1353 <210> 908 <211> 642 <212> DNA <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polynucleotide " <400> 908 gagatcgtga tgacccagtc ccccgccacc ctgtctgtgt ctcccggcga gagagccacc 60 ctgagctgca gagcctccga gtccgtgtcc tccaacgtgg cctggtatca gcagagacct 120 ggtcaggccc ctcggctgct gatctacggc gcctctaacc gggccaccgg catccctgcc 180 agattctccg gctccggcag cggcaccgac ttcaccctga ccatctcccg gctggaaccc 240 gaggacttcg ccgtgtacta ctgcggccag tcctactcat accccttcac cttcggccag 300 ggcaccaagc tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc 360 agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420 ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540 ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 600 ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642 <210> 909 <211> 5 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 909 Ser Tyr Gly Val Asp 1 5 <210> 910 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 910 Gly Phe Ser Leu Ser Ser Tyr 1 5 <210> 911 <211> 16 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 911 Val Ile Trp Gly Gly Gly Gly Thr Tyr Tyr Ala Ser Ser Leu Met Gly 1 5 10 15 <210> 912 <211> 5 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 912 Trp Gly Gly Gly Gly 1 5 <210> 913 <211> 13 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 913 His Ala Tyr Gly His Asp Gly Gly Phe Ala Met Asp Tyr 1 5 10 <210> 914 <211> 11 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 914 Arg Ala Ser Glu Ser Val Ser Ser Asn Val Ala 1 5 10 <210> 915 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 915 Ser Glu Ser Val Ser Ser Asn 1 5 <210> 916 <211> 7 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 916 Gly Ala Ser Asn Arg Ala Thr 1 5 <210> 917 <211> 3 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 917 Gly Ala Ser One <210> 918 <211> 9 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 918 Gly Gln Ser Tyr Ser Tyr Pro Phe Thr 1 5 <210> 919 <211> 6 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       peptide " <400> 919 Ser Tyr Ser Tyr Pro Phe 1 5 <210> 920 <211> 124 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 920 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr             20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val         35 40 45 Ala Val Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val     50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                 85 90 95 Ala Arg Gly Gly Ser Met Val Arg Gly Asp Tyr Tyr Tyr Gly Met Asp             100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser         115 120 <210> 921 <211> 107 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 921 Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala             20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile         35 40 45 Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly     50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Tyr                 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys             100 105 <210> 922 <400> 922 000 <210> 923 <400> 923 000 <210> 924 <400> 924 000 <210> 925 <400> 925 000 <210> 926 <400> 926 000 <210> 927 <400> 927 000 <210> 928 <400> 928 000 <210> 929 <400> 929 000 <210> 930 <400> 930 000 <210> 931 <400> 931 000 <210> 932 <400> 932 000 <210> 933 <400> 933 000 <210> 934 <400> 934 000 <210> 935 <400> 935 000 <210> 936 <400> 936 000 <210> 937 <400> 937 000 <210> 938 <400> 938 000 <210> 939 <400> 939 000 <210> 940 <400> 940 000 <210> 941 <400> 941 000 <210> 942 <400> 942 000 <210> 943 <400> 943 000 <210> 944 <400> 944 000 <210> 945 <400> 945 000 <210> 946 <400> 946 000 <210> 947 <400> 947 000 <210> 948 <400> 948 000 <210> 949 <400> 949 000 <210> 950 <400> 950 000 <210> 951 <400> 951 000 <210> 952 <400> 952 000 <210> 953 <400> 953 000 <210> 954 <400> 954 000 <210> 955 <400> 955 000 <210> 956 <400> 956 000 <210> 957 <400> 957 000 <210> 958 <400> 958 000 <210> 959 <400> 959 000 <210> 960 <400> 960 000 <210> 961 <400> 961 000 <210> 962 <400> 962 000 <210> 963 <400> 963 000 <210> 964 <400> 964 000 <210> 965 <400> 965 000 <210> 966 <400> 966 000 <210> 967 <400> 967 000 <210> 968 <400> 968 000 <210> 969 <400> 969 000 <210> 970 <400> 970 000 <210> 971 <400> 971 000 <210> 972 <400> 972 000 <210> 973 <400> 973 000 <210> 974 <400> 974 000 <210> 975 <400> 975 000 <210> 976 <400> 976 000 <210> 977 <400> 977 000 <210> 978 <400> 978 000 <210> 979 <400> 979 000 <210> 980 <400> 980 000 <210> 981 <400> 981 000 <210> 982 <400> 982 000 <210> 983 <400> 983 000 <210> 984 <400> 984 000 <210> 985 <400> 985 000 <210> 986 <400> 986 000 <210> 987 <400> 987 000 <210> 988 <400> 988 000 <210> 989 <400> 989 000 <210> 990 <400> 990 000 <210> 991 <400> 991 000 <210> 992 <400> 992 000 <210> 993 <400> 993 000 <210> 994 <400> 994 000 <210> 995 <400> 995 000 <210> 996 <400> 996 000 <210> 997 <400> 997 000 <210> 998 <400> 998 000 <210> 999 <400> 999 000 <210> 1000 <400> 1000 000 <210> 1001 <211> 114 <212> PRT <213> Homo sapiens <400> 1001 Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile 1 5 10 15 Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His             20 25 30 Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln         35 40 45 Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu     50 55 60 Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val 65 70 75 80 Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile                 85 90 95 Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn             100 105 110 Thr Ser          <210> 1002 <211> 170 <212> PRT <213> Homo sapiens <400> 1002 Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val 1 5 10 15 Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly             20 25 30 Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn         35 40 45 Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile     50 55 60 Arg Asp Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro Ser Thr Val 65 70 75 80 Thr Thr Ala Gly Val Thr Pro Gln Pro Glu Ser Leu Ser Pro Ser Gly                 85 90 95 Lys Glu Pro Ala Ala Ser Ser Pro Ser Ser Asn Asn Thr Ala Ala Thr             100 105 110 Thr Ala Ala Ile Val Pro Gly Ser Gln Leu Met Pro Ser Lys Ser Pro         115 120 125 Ser Thr Gly Thr Thr Glu Ile Ser Ser His Glu Ser Ser His Gly Thr     130 135 140 Pro Ser Gln Thr Thr Ala Lys Asn Trp Glu Leu Thr Ala Ser Ala Ser 145 150 155 160 His Gln Pro Pro Gly Val Tyr Pro Gln Gly                 165 170 <210> 1003 <211> 114 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 1003 Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile 1 5 10 15 Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His             20 25 30 Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln         35 40 45 Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu     50 55 60 Asn Leu Ile Ile Leu Ala Asn Asp Ser Leu Ser Ser Asn Gly Asn Val 65 70 75 80 Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile                 85 90 95 Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn             100 105 110 Thr Ser          <210> 1004 <211> 297 <212> PRT <213> Artificial Sequence <220> <221> source <223> / note = "Description of Artificial Sequence: Synthetic       polypeptide " <400> 1004 Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val 1 5 10 15 Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly             20 25 30 Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn         35 40 45 Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile     50 55 60 Arg Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 65 70 75 80 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys                 85 90 95 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val             100 105 110 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr         115 120 125 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu     130 135 140 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 145 150 155 160 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys                 165 170 175 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln             180 185 190 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu         195 200 205 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro     210 215 220 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 225 230 235 240 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu                 245 250 255 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val             260 265 270 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln         275 280 285 Lys Ser Leu Ser Leu Ser Pro Gly Lys     290 295 <210> 1005 <211> 114 <212> PRT <213> Homo sapiens <220> <221> MOD_RES <222> (93) .. (93) <223> Glu or Lys <400> 1005 Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile 1 5 10 15 Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His             20 25 30 Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln         35 40 45 Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu     50 55 60 Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val 65 70 75 80 Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Xaa Lys Asn Ile                 85 90 95 Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn             100 105 110 Thr Ser          <210> 1006 <211> 77 <212> PRT <213> Homo sapiens <400> 1006 Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val 1 5 10 15 Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly             20 25 30 Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn         35 40 45 Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile     50 55 60 Arg Asp Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro 65 70 75

Claims (62)

An anti-LAG-3 antibody molecule for use in a dose of about 300 mg to about 500 mg once every 3 weeks, or about 700 mg to about 900 mg once every 4 weeks to treat cancer in a subject,
A heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO: 701, the VHCDR2 amino acid sequence of SEQ ID NO: 702, and the VHCDR3 amino acid sequence of SEQ ID NO: 703; And a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 710, the VLCDR2 amino acid sequence of SEQ ID NO: 711, and the VLCDR3 amino acid sequence of SEQ ID NO: 712. . In a subject, comprising administering to the subject an anti-LAG-3 antibody molecule once every 3 weeks at a dose of about 300 mg to about 500 mg, or once every 4 weeks at a dose of about 700 mg to about 900 mg. How to treat cancer,
Wherein the anti-LAG-3 antibody molecule comprises a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO: 701, the VHCDR2 amino acid sequence of SEQ ID NO: 702, and the VHCDR3 amino acid sequence of SEQ ID NO: 703; And a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 710, the VLCDR2 amino acid sequence of SEQ ID NO: 711, and the VLCDR3 amino acid sequence of SEQ ID NO: 712. How to treat. The antibody molecule or method of claim 1 or 2, wherein the anti-LAG-3 antibody molecule is used once every three weeks at a dose of about 300 mg to about 500 mg. The antibody molecule or method of claim 3, wherein the anti-LAG-3 antibody molecule is used once every three weeks at a dose of about 400 mg. The antibody molecule or method of claim 1 or 2, wherein the anti-LAG-3 antibody molecule is used once every four weeks at a dose of about 700 mg to about 900 mg. The antibody molecule or method of claim 5, wherein the anti-LAG-3 antibody molecule is used once every four weeks at a dose of about 800 mg. The antibody molecule of any one of claims 1-6, wherein the antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 706 and a VL comprising the amino acid sequence of SEQ ID NO: 718. Way. The antibody molecule of any one of claims 1 to 7, wherein the antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 709 and a light chain comprising the amino acid sequence of SEQ ID NO: 721 or Way. The antibody molecule of any one of claims 1 to 6, wherein the antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 724 and a VL comprising the amino acid sequence of SEQ ID NO: 730 or Way. The antibody molecule according to any one of claims 1 to 6 and 9, wherein the antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 727 and a light chain comprising the amino acid sequence of SEQ ID NO: 733. Phosphorus antibody molecule or method. The antibody molecule or method according to any one of claims 1 to 10, wherein the cancer is a solid tumor or a blood cancer. The cancer according to any one of claims 1 to 11, wherein the cancer is brain cancer, pancreatic cancer, skin cancer, kidney cancer, breast cancer, virus-associated cancer, anal duct cancer, cervical cancer, stomach cancer, head and neck cancer, nasopharyngeal cancer (NPC), penile cancer. , Vaginal or vulvar cancer, colorectal cancer, lung cancer, leukemia, lymphoma, myeloma, or metastatic lesions of cancer. 13. The antibody molecule or method of claim 12, wherein the brain cancer is glioblastoma or neuroeducation. The antibody molecule or method of claim 12, wherein the skin cancer is melanoma or Merkel cell carcinoma. 13. The antibody molecule or method of claim 12, wherein the renal cancer is renal cell carcinoma (RCC). The antibody molecule or method of claim 12, wherein the breast cancer is breast carcinoma or triple negative breast cancer (TNBC). The antibody molecule or method of claim 12, wherein the virus-associated cancer is selected from anal canal cancer, cervical cancer, gastric cancer, head and neck cancer, nasopharyngeal cancer (NPC), penile cancer or vaginal or vulvar cancer. 13. The antibody molecule or method of claim 12, wherein the colorectal cancer is selected from microsatellite unstable colorectal cancer, microsatellite stable colorectal cancer, mismatch recovery proficient colorectal cancer, or mismatch repair deficient colorectal cancer. 13. The antibody molecule or method of claim 12, wherein the lung cancer is non-small cell lung cancer (NSCLC). The antibody molecule or method of claim 12, wherein the lymphoma is Hodgkin's lymphoma (HL) or diffuse versus B cell lymphoma (DLBCL). The antibody molecule or method of any one of claims 1 to 20, wherein the cancer is advanced cancer, metastatic cancer, recurrent cancer, recurrent cancer, or non-resectable cancer. 22. The antibody molecule or method of any one of claims 1 to 21, wherein the anti-LAG-3 antibody molecule is used in combination with a second therapeutic agent or modality. 23. The antibody molecule or method of any one of claims 1 to 22, wherein the anti-LAG-3 antibody molecule is used in combination with a PD-1 inhibitor. The PD-1 inhibitor of claim 23, wherein the PD-1 inhibitor is selected from PDR001, nivolumab, pembrolizumab, pidilizumab, MEDI0680, REGN2810, PF-06801591, BGB-A317, INCHR1210, TSR-042, or AMP-224. Antibody molecule or method. 25. The antibody molecule or method of claim 23 or 24, wherein the PD-1 inhibitor is used once every 3 weeks at a dose of about 300 mg or once every 4 weeks at a dose of about 400 mg. The antibody molecule or method of any one of claims 1 to 25, wherein the anti-LAG-3 antibody molecule is used in combination with a PD-L1 inhibitor. The antibody molecule or method of claim 26, wherein the PD-L1 inhibitor is selected from FAZ053, atezolizumab, abelumab, durvalumab, or BMS-936559. 28. The antibody molecule or method of any one of claims 1 to 27, wherein the anti-LAG-3 antibody molecule is used in combination with a chemotherapeutic agent. 29. The antibody molecule or method of claim 28, wherein the chemotherapeutic agent is selected from platinum agents and nucleotide analogs or precursor analogs. 30. The antibody molecule or method of claim 29, wherein the platinum agent is selected from carboplatin, cisplatin, oxaliplatin, or tetraplatin. 30. The antibody molecule or method of claim 29, wherein the nucleotide analog or precursor analog comprises capecitabine. The anti-LAG-3 antibody molecule of claim 1, wherein the anti-LAG-3 antibody molecule is used to treat cancer selected from NSCLC, melanoma, renal cancer, glioblastoma, virus-associated cancer, or colorectal cancer. Phosphorus antibody molecule or method. 33. The antibody molecule or method of claim 32, wherein the anti-LAG-3 antibody molecule is used in combination with an anti-PD-1 antibody molecule. 32. The antibody molecule or method of any one of claims 1 to 31, wherein the anti-LAG-3 antibody molecule is used to treat pancreatic cancer or breast cancer. The antibody molecule or method of claim 34, wherein the breast cancer is TNBC. The antibody molecule or method of claim 34 or 35, wherein the anti-LAG-3 antibody molecule is used in combination with an anti-PD-1 antibody molecule. The antibody molecule or method of any one of claims 34-36, wherein the anti-LAG-3 antibody molecule is used in combination with a chemotherapeutic agent. The antibody molecule or method of claim 37, wherein the chemotherapeutic agent is selected from platinum agents and nucleotide analogs or precursor analogs. The antibody molecule or method of claim 38, wherein the platinum agent is selected from carboplatin, cisplatin, oxaliplatin, or tetraplatin. The antibody molecule or method of claim 38, wherein the nucleotide analog or precursor analog comprises capecitabine. The antibody molecule or method of any one of claims 1-40, wherein the subject has or has been identified to have LAG-3 expression in tumor-infiltrating lymphocytes (TILs). The antibody molecule or method of any one of claims 1 to 41, wherein the subject has or has been confirmed to have cancer expressing PD-L1. An anti-LAG-3 antibody molecule for use once every three weeks at a dose of about 300 mg to about 500 mg or once every four weeks at a dose of about 700 mg to about 900 mg to treat cancer in a subject It includes a pharmaceutical composition or a dosage form,
Wherein the anti-LAG-3 antibody molecule comprises a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO: 701, the VHCDR2 amino acid sequence of SEQ ID NO: 702, and the VHCDR3 amino acid sequence of SEQ ID NO: 703; And a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 710, the VLCDR2 amino acid sequence of SEQ ID NO: 711, and the VLCDR3 amino acid sequence of SEQ ID NO: 712. . The pharmaceutical composition or dosage formulation of claim 43, wherein the dose is about 300 mg to about 500 mg once every three weeks. The pharmaceutical composition or dosage formulation of claim 43, wherein the dose is about 700 mg and about 900 mg once every 4 weeks. The pharmaceutical composition of any one of claims 43 to 45 wherein the antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 706 and a VL comprising the amino acid sequence of SEQ ID NO: 718. Dosage Formulation. The pharmaceutical composition according to any one of claims 43 to 46, wherein the antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 709 and a light chain comprising the amino acid sequence of SEQ ID NO: 721. Dosage Formulation. The pharmaceutical composition of any one of claims 43 to 45, wherein the antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 724 and a VL comprising the amino acid sequence of SEQ ID NO: 730, or Dosage Formulation. The antibody molecule of any one of claims 43 to 45 and 48, wherein the antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 727 and a light chain comprising the amino acid sequence of SEQ ID NO: 733. Phosphorus pharmaceutical composition or dosage form. 50. A pharmaceutical composition or dosage formulation according to any one of claims 43 to 49 for use in treating cancer. The pharmaceutical composition or dosage formulation according to claim 50, wherein the cancer is a solid tumor or a blood cancer. 52. The method of claim 50 or 51, wherein the cancer is brain cancer, pancreatic cancer, skin cancer, renal cancer, breast cancer, virus-associated cancer, anal canal cancer, cervical cancer, stomach cancer, head and neck cancer, nasopharyngeal cancer (NPC), penile cancer, vagina or vulva. Pharmaceutical compositions or dosage formulations selected from cancer, colorectal cancer, lung cancer, leukemia, lymphoma, myeloma, or metastatic lesions of cancer. (a) at least 50% of soluble LAG-3 in serum or serum samples from a subject is bound by an anti-LAG-3 antibody molecule; Or (b) the subject in a dose or dose schedule in which at least 90% of the membrane-bound LAG-3 in a cancer or cancer sample from the subject is bound by an anti-LAG-3 antibody molecule, or both. Anti-LAG-3 antibody molecule for use in treating cancer in cancer. (a) at least 50% of soluble LAG-3 in serum or serum samples from a subject is bound by an anti-LAG-3 antibody molecule; Or (b) the subject in a dose or dose schedule in which at least 90% of the membrane-bound LAG-3 in a cancer or cancer sample from the subject is bound by an anti-LAG-3 antibody molecule, or both. A method of treating cancer in a subject, comprising administering an anti-LAG-3 antibody molecule to the subject. 55. The method of claim 53 or 54, wherein the dosage schedule comprises: (a) at least 60% of soluble LAG-3 in the serum or serum sample from the subject is bound by an anti-LAG-3 antibody molecule; Or (b) at least 90% of the membrane-bound LAG-3 in a cancer or cancer sample from a subject generates one or both of those bound by an anti-LAG-3 antibody molecule. The dosage schedule of any one of claims 53 to 55, wherein the dosage schedule is (a) at least 70% of soluble LAG-3 in the serum or serum sample from the subject is bound by an anti-LAG-3 antibody molecule. ; Or (b) at least 90% of the membrane-bound LAG-3 in a cancer or cancer sample from a subject generates one or both of those bound by an anti-LAG-3 antibody molecule. The VHCDR1 amino acid sequence of SEQ ID NO: 701, the VHCDR2 amino acid sequence of SEQ ID NO: 702, and the VHCDR3 of SEQ ID NO: 703 according to any one of claims 53 to 56. Heavy chain variable region (VH) comprising an amino acid sequence; And a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 710, the VLCDR2 amino acid sequence of SEQ ID NO: 711, and the VLCDR3 amino acid sequence of SEQ ID NO: 712. The antibody molecule of any one of claims 53-57, wherein the antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 706 and a VL comprising the amino acid sequence of SEQ ID NO: 718. Way. The antibody molecule according to any one of claims 53 to 58, wherein the antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 709 and a light chain comprising the amino acid sequence of SEQ ID NO: 721. Way. The antibody molecule of any one of claims 53-57, wherein the antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 724 and a VL comprising the amino acid sequence of SEQ ID NO: 730, or Way. The antibody molecule of any one of claims 53 to 57 and 60, wherein the antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 727 and a light chain comprising the amino acid sequence of SEQ ID NO: 733. Phosphorus antibody molecule or method. The anti-LAG-3 antibody molecule of any one of claims 54-61, wherein the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to about 500 mg or four weeks at a dose of about 700 mg to about 900 mg. An antibody molecule or method that is administered once per time.